MICR 270 Module 4 Companion Guide PDF

MICR 270 INFECTION, IMMUNITY, AND INFLAMMATION MODULE 04 ADVERSE REACTIONS AND IMMUNE DEFECTS Please note: This course was designed to be interacted and engaged with using the online modules. This Module Companion Guide is a resource created to complement the online slides. If there is a discrepancy between this guide and the online module, please refer to the module. How can you help protect the integrity and quality of your Queen’s University course? Do not distribute this Module Companion Guide to any students who are not enrolled in MICR 270 as it is a direct violation of the Academic Integrity Policy of Queen’s University. Students found in violation can face sanctions. For more information, please visit https://www.queensu.ca/academic- calendar/health-sciences/bhsc/. MODULE 04 COMPANION GUIDE MICR 270 TABLE OF CONTENTS INTRODUCTION..................................................................................................................................................... 4 Introduction....................................................................................................................................................... 4 Course Toolbox.................................................................................................................................................. 4 Learning Outcomes........................................................................................................................................... 5 Module Assignments........................................................................................................................................ 5 Journal Article Assignment........................................................................................................................... 5 Scientific Poster Assignment........................................................................................................................ 6 Module Outline.................................................................................................................................................. 6 SECTION 01: Immunodeficiency.......................................................................................................................... 7 Immunodeficiency............................................................................................................................................. 7 Classification of Primary Immunodeficiencies............................................................................................... 8 Secondary Immunodeficiency: The Case of HIV /AIDS................................................................................11 Mode of Transmission of HIV.........................................................................................................................11 HIV and the Immune Response......................................................................................................................12 Antiretroviral Therapy: A New Era for HIV-infected Patients.....................................................................13 Question: Primary Immunodeficiencies.......................................................................................................14 Screening Techniques for Immunodeficiencies...........................................................................................15 Complete Blood Counts.............................................................................................................................16 Infection vs. Immunodeficiency.....................................................................................................................16 Clinical History and Initial Examination........................................................................................................17 Question: Testing the Immune Response....................................................................................................17 Test Results......................................................................................................................................................18 Question: Further Analysis of the Immune Response................................................................................19 Question: Further Analysis of the Immune Response................................................................................19 Blood Test Results...........................................................................................................................................19 Question: Interpreting Negative Test Results..............................................................................................19 Activity: Diagnosis............................................................................................................................................20 Question: Explaining the Immune Response...............................................................................................20 SECTION 02: Autoimmunity................................................................................................................................22 Autoimmunity..................................................................................................................................................22 By The Numbers..............................................................................................................................................22 INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 1 MODULE 04 COMPANION GUIDE MICR 270 Classification of Autoimmune Diseases.......................................................................................................23 Graves Disease............................................................................................................................................23 Cause and Symptoms of Graves Disease.................................................................................................24 Rheumatoid Arthritis..................................................................................................................................24 Question: How Can We Cure or Treat Autoimmunity?...............................................................................24 Treatment of Autoimmune Diseases............................................................................................................25 Immunosuppressants and Organ Transplants............................................................................................25 Video: Clinical Focus on Organ Transplants.................................................................................................26 Classes of Immunosuppressive Drugs..........................................................................................................26 Activity: Mechanism of Immunosuppressive Drugs....................................................................................27 The Downsides to Immunosuppressive Drugs............................................................................................27 Impact of Immunosuppression on the Host................................................................................................28 Opportunistic Infections.................................................................................................................................28 The Impact of Immunosuppressive Drugs...................................................................................................29 SECTION 03: Hypersensitivity.............................................................................................................................31 Classification of Hypersensitivities................................................................................................................31 Type I Hypersensitivity....................................................................................................................................31 Type II Hypersensitivity...................................................................................................................................33 Type III Hypersensitivity..................................................................................................................................34 Type IV Hypersensitivity.................................................................................................................................35 Hypersensitivity - Patient Case #1.................................................................................................................36 Hypersensitivity - Patient Case #1 Test Results...........................................................................................38 Question: Hypersensitivity (1)........................................................................................................................38 Question: Hypersensitivity (2)........................................................................................................................39 Hypersensitivity - Patient Case #1 Diagnosis...............................................................................................39 Question: Hypersensitivity (3)........................................................................................................................39 Question: Patient Case #1 Explaining the Immune Response...................................................................40 Hypersensitivity - Patient Case #2 Introduction..........................................................................................40 Hypersensitivity - Patient Case # 2 Medical History....................................................................................41 Hypersensitivity - Patient Case #2 Social and Family History....................................................................41 Hypersensitivity - Patient Case #2 Physical Examination...........................................................................42 Hypersensitivity - Patient Case #2 Diagnosis...............................................................................................42 Hypersensitivity - Patient Case #2.................................................................................................................42 INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 2 MODULE 04 COMPANION GUIDE MICR 270 Question: Patient Case #2 Explainig the Immune Response.....................................................................43 CONCLUSION.......................................................................................................................................................44 Module Summary............................................................................................................................................44 Concept Map: List of Immunology Terminology..........................................................................................44 Learning Outcomes.........................................................................................................................................44 Module Assignments......................................................................................................................................45 Journal Article Assignment.........................................................................................................................45 Scientific Poster Assignment......................................................................................................................45 Module Complete............................................................................................................................................46 INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 3 MODULE 04 COMPANION GUIDE MICR 270 INTRODUCTION Please see the online learning module for the full experience of interactions within this document. INTRODUCTION This content was retrieved from Introduction, Slide 1 of 5 of the online learning module. In previous modules, you have learned about the normal functioning of the immune system as a cohesive unit. Of course, this is the best case scenario, however, the immune system itself can have defects. In Module 4, you will learn about immunodeficiencies, autoimmunity, and hypersensitivities. These conditions are broadly referred to as adverse reactions of the immune system or defects within the immune system that result in disease or disorder. In Module 4, you will learn about immunodeficiencies, autoimmunity, and hypersensitivities. These conditions are broadly referred to as adverse reactions of the immune system or defects within the immune system that result in disease or disorder. The concepts explored in Module 4 will be assessed through the Module 4 Quiz and will help you understand and present your journal article if you are assigned to choose an article for this module. Furthermore, working through Module 4 will provide you with enough information to begin working on your Scientific Poster assignment; you will be assigned your group members and topic mid-way through this module. COURSE TOOLBOX This content was retrieved from Introduction, Slide 2 of 5 of the online learning module. During the course, you will encounter some features that will help you enhance your understanding of course concepts. You will find the following icons throughout the modules: Orange Bolded Words: Throughout the modules you will find hover definitions*. Every time you see this feature, make sure you hover over the text to see a definition or additional information. View more information When you click this icon, it will reveal more details about a word or a concept covered in the course. Reveal part of an analogy created to help you understand the complexity of the immune system. Prison Break: INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 4 MODULE 04 COMPANION GUIDE MICR 270 The immune system response to an infection can be compared to someone trying to break out of prison. Each time you see this icon, click to learn more about what these components or processes would be in the analogy of a prison breakout situation. Definition*: Hover definition: I’m some additional information! LEARNING OUTCOMES This content was retrieved from Introduction, Slide 3 of 5 of the online learning module. At the end of Module 4, you will be able to: Compare and contrast primary and secondary immunodeficiencies. Hypothesize why HIV patients are so susceptible to infection. Compare and contrast autoimmunity and immunodeficiency using contemporary examples of diseases and disorders. Explain the four types of hypersensitivity reactions and their specific characteristics. Define allergens and how they cause an allergic reaction. MODULE ASSIGNMENTS This content was retrieved from Introduction, Slide 4 of 5 of the online learning module. These assignments are associated to Module 4. Journal Article Assignment - Refer to pages 5-6 Scientific Poster Assignment - Refer to page 6 Module 4 Quiz Visit your course page to view the details of these assignments. Note on Activities Throughout the Module: Note that text responses and interactions will not be graded unless otherwise notified. However, they are recorded in the module and viewable by your instructors. JOURNAL ARTICLE ASSIGNMENT Subpage of Introduction, Slide 4 of 5 – Journal Article Assignment 1/1 In your group from the previous Journal Article Assignment, the seminar Leader for this module will choose one of the provided articles to write a summary about and create a narrated PowerPoint presentation summarizing the most important aspects of the article as it relates to module content. The seminar Leader will share this summary and presentation with their group. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 5 MODULE 04 COMPANION GUIDE MICR 270 The seminar Peer Reviewers will be responsible for reading the article summary, watching the narrated presentation, and providing constructive feedback using a provided rubric to grade the presentation. The seminar Leader will be given the opportunity to provide commentary on the feedback received. Visit your course page for more details. SCIENTIFIC POSTER ASSIGNMENT Subpage of Introduction, Slide 4 of 5 – Scientific Poster Assignment 1/1 The purpose of this assignment is to evaluate scientific research that is specific to an infectious disease and relate it your current understanding of the host immune mechanisms used to control the pathogen. This is a small group assignment. You will have a window of time during the semester within which to choose your group members. After the window is closed, all students without a group will randomly assigned a group. Each group will be assigned a disease from a designated list. Each group must create a scientific poster about their assigned disease with the goal of effectively teaching a peer about the immunological underpinnings of this disease. Once your poster is compiled, create and record 5 to 10-minute oral summary of your poster that guides the viewer through each section. This should be similar in style to if you were presenting at a poster fair and geared towards informing a peer in this course. MODULE OUTLINE This content was retrieved from Introduction, Slide 5 of 5 of the online learning module. Section 01: IMMUNODEFICIENCY Section 02: AUTOIMMUNITY Section 03: HYPERSENSITIVITY INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 6 MODULE 04 COMPANION GUIDE MICR 270 SECTION 01: IMMUNODEFICIENCY IMMUNODEFICIENCY This content was retrieved from Section 01, Slide 1 of 18 of the online learning module. An immunodeficiency is a disorder or condition where the immune system has reduced function or is absent and can be traced to the failure of one or more parts of the immune system. There are two main types of immunodeficiencies: primary and secondary. Learn the main differences between the two types. Primary Immunodeficiency Primary immunodeficiencies are congenital* and derive from a genetic or developmental defect leading to abnormal maturation of the immune system. Primary immunodeficiencies may be associated with defects in the innate or adaptive immune systems. The pie chart displays the relative distribution of primary immunodeficiencies accordingly to the faulty component(s). Primary immunodeficiencies are rare, but why? Primary immunodeficiencies are rare because in most cases, the foetus will not survive the defect. Secondary Immunodeficiency Secondary immunodeficiencies are acquired and result from environmental factors affecting and compromising the immune system. Causes of secondary immunodeficiency include: Undergoing chemotherapy treatment Taking immunosuppressive medication Contracting a chronic infection o E.g. HIV/AIDS Developing cancer o E.g. Leukemia, multiple myeloma and lymphoma What is the most well-studied secondary immunodeficiency? Acquired Immunodeficiency Syndrome (AIDS) was clinically first observed in 1981, while the causative agent, called Human Immunodeficiency Virus (HIV), was identified in 1983. Worldwide to date, the total number of people infected with HIV since 1981 is over 70 million, of whom over 35 million have died. Definition: Congenital: Present from birth INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 7 MODULE 04 COMPANION GUIDE MICR 270 CLASSIFICATION OF PRIMARY IMMUNODEFICIENCIES This content was retrieved from Section 01, Slide 2 of 18 of the online learning module. One of the more convenient ways to group the primary immunodeficiencies is according to the faulty component of the immune system. Explore each type of primary immunodeficiency. B-cell deficiencies Switch between an overview and a clinical example of each deficiency. Overview B-cell deficiencies are characterized by dysfunctional B lymphocytes or a decrease in their prevalence. Recall that B lymphocytes are the key cells of humoral immunity as they produce large quantities of antibodies. Therefore, a deficiency in B-cell development results in an increased susceptibility to infection, especially by encapsulated bacteria*. The first symptoms generally appear around the age of 7-9 months old. Why at this specific time? During pregnancy and the breastfeeding period, the mother transfers IgGs to the baby. It is around the age of 7-9 months that the antibody pool from the mother decreases, and because of B-cell deficiency, the infant is not able to synthesize normal levels of antibodies to compensate. Clinical Example X-LINKED AGAMMAGLOBULINEMIA (XLA) One example of a B cell deficiency is X-linked agammaglobulinemia (XLA), a rare genetic disorder. XLA is both X-linked and recessive, therefore it occurs almost exclusively in males. Patients with this disease do not develop mature B cells and, as a result, have extremely low levels of Ig G and lack all other immunoglobulins. While XLA patients are extremely susceptible to bacterial infections, their susceptibility to viral and fungal infections remains unchanged. This is because their cell-mediated immune responses remain normal. T-cell deficiencies Switch between an overview and a clinical example of each deficiency. Overview T-cell deficiencies are characterized by dysfunctional T lymphocytes or a decrease in their prevalence. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 8 MODULE 04 COMPANION GUIDE MICR 270 Recall that T lymphocytes are the key cells of cell-mediated immunity as they kill infected or abnormal cells. Therefore, a deficiency in T-cell development results in an increased susceptibility to viruses, protozoans, and fungi. T-cell deficiencies are often characterized by frequent infections beginning 3-4 months after birth. Some examples of these infections are pneumonia and candidiasis. Clinical Example DIGEORGE SYNDROME An example of a T cell deficiency is DiGeorge Syndrome, a complex disease caused by the deletion of a small segment of chromosome 22. DiGeorge Syndrome patients have an absent or underdeveloped thymus, which results in the absence of mature T cells. In addition to T-cell abnormalities, abnormalities in the heart, face and palate are commonly observed as well as learning disabilities. Complement deficiencies Switch between an overview and a clinical example of each deficiency. Overview The complement system performs multiple functions and involves the intricate regulation of nine components. Genetic deficiencies have been described for each of these complement components. Patients with complement deficiencies are prone to frequent severe bacterial infections and complications arising from inability to clear immune complexes. In particular, those with C3 (circled in diagram) deficiencies display the severest symptoms, reflective of the central role played by this component in complement activities. Clinical Example HEREDITARY ANGIOEDEMA (HAE) Complement deficiencies can also arise from deficiencies in proteins that regulate complement pathways. Patients with hereditary angioedema (HAE) lack a regulator of C1. Symptoms of HAE include swelling of the face, lips, larynx, or GI tract. The swelling of the larynx or GI tract are of particular concern because this can lead to suffocation or acute abdominal pain. Phagocytic deficiencies Switch between an overview and a clinical example of each deficiency. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 9 MODULE 04 COMPANION GUIDE MICR 270 Overview Recall that the phagocytic process is an important part of innate immunity, as extracellular pathogens are engulfed and destroyed within a phagocyte. Phagocytic deficiencies can appear at various stages of this process. In patients with defective phagocytes, bacterial and fungal infections are unusually frequent and severe, often causing deep abscesses. Clinical Example CHRONIC GRANULOMATOUS (CGD) An example of phagocytic deficiencies is Chronic Granulomatous Disease (CGD). In this rare inherited disease, the body’s phagocytes do not make the chemicals needed to kill phagocytosed bacteria. CGD derives its name from the tendency of patients with this disease to form non-malignant granulomas* in order to attempt separate foreign materials from the rest of the body. Combined T- and B-cell deficiencies Switch between an overview and a clinical example of each deficiency. Overview Individuals with combined T-cell and B-cell deficiencies have dysfunctional and/or low numbers of lymphocytes. As a result, both the humoral and cell-mediated responses of the adaptive immune system are compromised. This deficiency is characterized by little or no resistance to infection thus pathogens that cause mild diseases in the average human (such as chickenpox) may be life threatening. Patients with combined T- cell and B-cell deficiencies often suffer fatal infections within the first year of life. Clinical Example SEVERE COMBINED INHERITED IMMUNODEFICIENCY (SCID) Severe combined inherited immunodeficiency (SCID) is a classic example of a combined T-cell and B- cell deficiency. David Vetter suffered from SCID and was raised in a “bubble” for 12 years – for which he was referred to as “Bubble Boy” by the media. He never encountered any infections due to the sterile room that he live in, however a space suit invented by NASA allowed him to venture a short distance away from the room. David passed away in 1984 at the age of 12, after a bone marrow transplant (intended to treat his disease) contained an unexpected infectious agent. The Bubble Boy INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 10 MODULE 04 COMPANION GUIDE MICR 270 David Vetter, the bubble boy. Watch a short newsclip about his story. Definitions*: Encapsulated bacteria: Encapsulated bacteria encompass both Gram-positive and Gram-negative bacteria with the unifying feature being the production of capsule composed of polysaccharides. Non-malignant granulomas: Small, nodular aggregations of immune cells. Page Link: https://www.youtube.com/embed/pJa6KVLwl9U SECONDARY IMMUNODEFICIENCY: THE CASE OF HIV /AIDS This content was retrieved from Section 01, Slide 3 of 18 of the online learning module. Secondary immunodeficiencies are not as easily classified as primary deficiencies. As mentioned, the most well-known and studied secondary immunodeficiency disease is AIDS. Within a year of the first reported cases, in 1981 the U. S. Centre for Disease Control and Prevention (CDC) coined the term acquired immunodeficiency syndrome (AIDS) for this new disease. It can be defined by describing the combination of words used to make up its name. Learn about each word of the acronym “AIDS”. Acquired Individuals do not inherit this type of disease, which is a major difference between AIDS and the previously discussed primary immunodeficiency diseases. Immunodeficiency The one disease characteristic AIDS victims have in common is the breakdown of their immune system. Syndrome The plethora of rare but ravaging diseases that take advantage of the body’s collapsed defences. AIDS is the final stage following an acute and chronic HIV infection. Many AIDS patients die from opportunistic infections as their immune system is compromised and unable to effectively protect and defend the body. MODE OF TRANSMISSION OF HIV This content was retrieved from Section 01, Slide 4 of 18 of the online learning module. The mode of transmission of HIV varies depending on location. Use the map of the world to discover the most common mode of transmission of HIV in different areas around the globe. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 11 MODULE 04 COMPANION GUIDE MICR 270 Regardless of the portal of entry of HIV into the body, without treatment the outcome is the same - immunosuppression, neuropsychiatric abnormalities, and death. In North America, sexual intercourse is the primary mode of transmission. In Eastern Europe and Central Asia, the use of non-sterile injecting drug paraphernalia is the primary mode of transmission. In sub-Saharan Africa, the primary mode of HIV transmission is through heterosexual sex with a concomitant epidemic in children through vertical transmission (mother-to-child). HIV AND THE IMMUNE RESPONSE This content was retrieved from Section 01, Slide 5 of 18 of the online learning module. Learn the stages of HIV infection. 0. PRIMARY INFECTION Upon infection with HIV, most people will mount an effective immune response to the virus for the first couple weeks. However, over time, this response will prove ineffective through the various stages of the disease, as the HIV virus compromises the individual's immune system. 1. ACUTE INFECTION During acute infection, HIV targets and infects cells with CD4 on their surface, including CD4+ helper T cells. Viral infection causes a drastic decrease in the level of CD4+ helper T cells while the level of virus in the blood increases. Within 2 to 4 weeks after primary exposure to HIV, some people will experience flu-like symptoms including fever, headache, and rash. The level of HIV in the blood is very high during the acute infection phase, which greatly increases the risk of HIV transmission. Why do CD4+ cell levels stop crashing? Note that CD4+ helper T-cell levels increase after the initial decrease, as some antibodies are formed against the virus allowing the immune system to recover some of the lost cell population. 2. CLINICAL LATENCY During this stage of the disease, HIV continues to multiply in the body at a steady state. People with chronic HIV infection often do not experience any HIV-related symptoms, however transmission is still possible. Anti-HIV antibodies are detectable during this phase of the infection. However, HIV can begin to evade the immune response that is present by changing their antigens through high mutation rates. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 12 MODULE 04 COMPANION GUIDE MICR 270 The length of this phase can vary but is generally about 8 to 10 years. 3. AIDS Throughout clinical latency, CD4+ T helper cells get ‘exhausted’ and depleted while constantly fighting a chronic HIV infection. HIV patients are diagnosed with AIDS if they have a CD4+ helper T cell level of less than 200 cells/m m3. After this point, viral load drastically increases as the virus continues to acquire mutations that allow it to further avoid immune defenses. As the immune system is severely weakened, patients become extremely susceptible to opportunistic infections. In the absence of treatment, AIDS patients typically survive about 3 years. ANTIRETROVIRAL THERAPY: A NEW ERA FOR HIV-INFECTED PATIENTS This content was retrieved from Section 01, Slide 6 of 18 of the online learning module. The first antiretroviral therapy was approved in 1987. These drugs do not kill or cure the human immunodeficiency virus, but prevent it from replicating. Since then, combination retroviral therapy, known as antiretroviral therapy (ART) or highly active antiretroviral therapy (HAART) has been introduced. This therapy utilizes a panel of antiretroviral drugs in different combinations to prevent drug resistance by the rapidly-mutating virus. This treatment method has led to staggering declines in the rates of AIDS and AIDS-associated deaths. HAART maintains function of the immune system, and prevents opportunistic infections that often lead to death. According to the WHO, an estimated 700 000 lives were saved in 2010 alone due to the increased availability of antiretroviral therapy in low- and middle-income countries. Ever since the implementation of HAART, HIV almost never progresses into AIDS and results in substantially fewer deaths than the pre-HAART era, a substantial feat considering untreated AIDS patients typically die in 3 years. © U.S. Department of Health and Human Services. References: INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 13 MODULE 04 COMPANION GUIDE MICR 270 Antiretroviral Therapy: What Does It Do? (2016, July 20). Retrieved from https://aidsinfo.nih.gov/understanding-hiv-aids/infographics/2/antiretroviral-therapy--what-does-it-do- Fauci AS, Folkers GK. Toward an AIDS-Free Generation. JAMA. 2012;308(4):343-344. doi:10.1001/jama.2012.8142 [https://jamanetwork.com/journals/jama/fullarticle/1221711] World Health Organization; UNAIDS; UNICEF. Global HIV/AIDS response: epidemic update and health sector progress towards universal access: progress report 2011. Geneva, Switzerland: WHO; 2011. http://whqlibdoc.who.int/publications/2011/9789241502986_eng.pdf. Accessed June 10, 2012 Kanters, S., MSc, Vitoria, M., MD, Doherty, M., MD, Socias, M. E., MD, Ford, N., PhD, Forrest, J. I., MPH,... Mills, E. J., Dr. (2016). Comparative efficacy and safety of first-line antiretroviral therapy for the treatment of HIV infection: A systematic review and network meta-analysis. Lancet HIV, the, 3(11), e510-e520. doi:10.1016/S2352-3018(16)30091-1 [https://journals.scholarsportal.info/pdf/23523018/v03i0011/e510_ceasofasranm.xml] Moore, R.,&Chaisson, R. (1999). Natural history of HIV infection in the era of combination antiretroviral therapy. Aids, 13(14), 1933-1942. doi:10.1097/00002030-199910010-00017 QUESTION: PRIMARY IMMUNODEFICIENCIES This content was retrieved from Section 01, Slide 7 of 18 of the online learning module. Associate the correct answers to each type of primary immunodeficiency. Select the terms from the word bin into the appropriate category to review your knowledge of primary immunodeficiencies. Word Bin: All infectious agents, Antibodies, Bacteria infections (accumulation of immune complexes), Bacterial infections, Cell-mediated immunity, Chronic granulomatous disease (CGD), DiGeorge Syndrome, Frequent, severe bacterial and fungal infections (deep abscesses), Hereditary angioedema (HA E), Innate immunity, Lymphocytes, Proteins C1 to C9, Severe combined immunodeficiency (SCID), Viruses, protozoan, and fungal infections, X-linked agammaglobulinemia (XLA) Immunodeficiency Increased Immune Example of disease: Group susceptibility to… component(s) compromised: B- and T-cell deficiencies Complement deficiencies T-cell deficiencies Phagocytic deficiencies B-cell deficiencies INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 14 MODULE 04 COMPANION GUIDE MICR 270 Feedback: Immunodeficiency Increased Immune Example of disease: Group susceptibility to… component(s) compromised: B- and T-cell All infectious agents Lymphocytes Severe combined deficiencies immunodeficiency (SCI D) Complement Bacteria infections Proteins C1 to C9 Hereditary deficiencies (accumulation of angioedema (HA E) immune complexes) T-cell deficiencies Viruses, protozoan, Cell-mediated DiGeorge Syndrome and fungal infections immunity Phagocytic Frequent, severe Innate immunity Chronic deficiencies bacterial and fungal granulomatous infections (deep disease (CGD) abscesses) B-cell deficiencies Bacterial infections Antibodies X-linked agammaglobulinemia (XLA) SCREENING TECHNIQUES FOR IMMUNODEFICIENCIES This content was retrieved from Section 01, Slide 8 of 18 of the online learning module. Screening techniques are methods or strategies used to identify the possible presence of a disease in individuals who may be pre-symptomatic or have unrecognized symptoms of the disease. This allows for early intervention and management of the disease in an effort to reduce suffering and/or mortality. There are two major screening methods for primary and secondary immunodeficiency. Learn about these screening methods. Complete Blood Counts - Refer to page 16 Complete Blood Counts (CBC) show how many of each cell type are present in a small sample of patients’ blood. These numbers are then compared to a reference range of values commonly found in healthy people. This technique is used to highlight any severe defects in the blood that could potentially be caused by an immunodeficiency. CBCs are readily available to physicians and are often used to guide the use of more detailed tests of specific cell types. Quantitative Serum Immunoglobulin Quantitative serum immunoglobulin tests measure the levels of IgG, IgA, and IgM in a patient's blood serum and compare them to a control. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 15 MODULE 04 COMPANION GUIDE MICR 270 If the levels of antibodies in the blood are lower than normal (hypogammaglobulinemia), this could be an indication of a humoral immunodeficiency. Further testing such as complete blood counts and urine protein electrophoresis* can be used to pinpoint the source of the hypogammaglobulinemia. Definition*: Urine protein electrophoresis: A screening test to evaluate the amount of certain proteins in urine. COMPLETE BLOOD COUNTS Subpage of Section 01, Slide 8 of 18 – Complete Blood Counts 1/1 The image depicts a typical sheet of results of a CBC. Please note that you are not required to memorize the specifics of a CBC sheets. Use the column titles to explore each element of the reference table. Test This column shows what cell types were tested; for example, WBC stands for white blood cell, RBC for Red Blood Cell. You may be able to guess what the other acronyms stand for! Result The actual results of the test are displayed in this column. Units The units for both the results and reference ranges are displayed in the third column. Units often vary between cell types; they may be concentrations (g/d L, cells/m m3), proportions (%) or other types of units. This ensures that the results are displayed in the most practical and meaningful way. Ref. Range Reference ranges represent the range of values that are considered normal in a relevant population. Reference values may differ between health care facilities due to variance in instrumentation and assay protocols. The validity of the results is ensured through accreditation by the International Organization for Standardization (ISO). INFECTION VS. IMMUNODEFICIENCY This content was retrieved from Section 01, Slide 9 of 18 of the online learning module. Examine the following case study that demonstrates a characteristic diagnosis of an immunodeficiency. By reviewing clinical history and blood testing, one can examine the result of secondary immunodeficiency reactions. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 16 MODULE 04 COMPANION GUIDE MICR 270 While you read through the case study, think about what tests can be used to diagnose immunodeficiencies and the immune response in these diseases. Use this case study as an opportunity to solidify your understanding of concepts learned throughout the course, as well as an opportunity to gain new knowledge that you can apply within your current knowledge framework. David, a 20 year old male, visited his family physician who has been treating him for years. David tells his doctor that for the last week he has been feeling under the weather, he’s mainly feeling fatigue, feverish, and has had some muscle aches and a sore throat. David thinks it is just the flu, but decides to get it check out since none of his friends are sick and its unusual for him to get the flu in the middle of summer. CLINICAL HISTORY AND INITIAL EXAMINATION This content was retrieved from Section 01, Slide 10 of 18 of the online learning module. Review each stage of examination to learn more about David’s diagnosis. Review of Symptoms Upon review of his symptoms, David reports a temperature of 38.0 degrees Celsius, but denies chills, weight loss, night sweats, or appetite change. He also describes a mild irritation of his eyes, a sore throat, and swollen lymph nodes in his neck. Enlarged lymph nodes suggest the problem is likely systemic. Clinical Findings Upon examination, David appears relatively well. His temperature is slightly elevated at 38.3 degrees Celsius, but his heart rate, respiratory rate, and blood pressure are normal. The lymph nodes in his neck and groin are both swollen and palpable and he has a sore throat - suggesting a picture consistent with mononucleosis*. Clinical History Upon speaking with David, the family doctor finds out that he has a history of alcohol and tobacco use. David denies any IV drugs. He is currently in a monogamous relationship with his girlfriend for the last three months and reports that they have recently started having unprotected sex. He denies any history of sexually transmitted infections. Based on his history, it appears that the symptoms are acute rather than chronic. Definition*: Mononucleosis: A contagious infectious disease often caused by Epstein-Barr virus (EBV). Most commonly spread by saliva, giving it the nick-name of ‘kissing disease’. The incubation period is four to eight weeks and causes a glandular fever and extended feeling of tiredness even months after the initial infection is resolved. QUESTION: TESTING THE IMMUNE RESPONSE INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 17 MODULE 04 COMPANION GUIDE MICR 270 This content was retrieved from Section 01, Slide 11 of 18 of the online learning module. Answer the following question based on the case study you just read. Based on the information you have learned in the module, which tests should the physician use to test David’s immune status? What viral infections are associated with a mononucleosis presentation? You may need to do some independent research to answer this question. Feedback: The physician should run screening tests such as a complete blood count, to highlight for any deficiencies in the blood that may be accounted for by a primary or secondary immune deficiency, and I g serum levels, to detect for low levels of antibodies in the circulation. Infectious mononucleosis is a feature of primary cytomegalovirus (CMV), EBV, as well as HIV infection. TEST RESULTS This content was retrieved from Section 01, Slide 12 of 18 of the online learning module. In addition to David’s immune response, the physician also decided to test for strep throat and to ensure that his blood and liver enzymes were stable. Consider what the test results could indicate with respect to the immune system function. Read the result of each test performed. Complete Blood Counts (CBC) WBC result: 3.0 K/u L WBC normal range: 4.8-10.8 K/u L David’s white blood count* (WBC) is low. Note: Clinically, a low WBC is indicative of a weakened immune response. This means that there is a decreased number of white blood cells present to fight infection and these individuals are often left more susceptible to disease. Hemoglobin Normal. Other Tests Rapid strep test and throat culture Negative. Liver enzyme tests Are elevated suggesting liver inflammation. Serology for EBV and CMV INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 18 MODULE 04 COMPANION GUIDE MICR 270 EBV test for Mononucleosis - Negative IgG for CMV - Positive IgM for CMV – Negative Definition*: White blood count: The count of all immune cells, also called white blood cells or leukocytes. QUESTION: FURTHER ANALYSIS OF THE IMMUNE RESPONSE This content was retrieved from Section 01, Slide 13 of 18 of the online learning module. Answer the following question based on the test results you just read. How would you interpret the CMV serology? Feedback: The presence of IgG and not IgM suggests that David is CMV seropositive from before and did not recently contract CMV - in this case CMV is not the cause of his mononucleosis picture. QUESTION: FURTHER ANALYSIS OF THE IMMUNE RESPONSE This content was retrieved from Section 01, Slide 14 of 18 of the online learning module. Answer the following question based on the case study you just read. Normally, in case of infection the level of white blood cells is higher, not lower than the control. As indicated in the blood test, David has a low WBC and elevated liver enzymes. Further analysis revealed his helper T-cell count is 300 cells per cubic millimeter. A normal helper T-cell count is between 500 and 1,500 cells per cubic millimeter. What disease could this result from? Feedback: David’s doctor is now worried that David may have acquired HIV, and decides to test him for HIV. BLOOD TEST RESULTS This content was retrieved from Section 01, Slide 15 of 18 of the online learning module. In a confidential counselling session with David, the doctor discusses testing him for Human Immunodeficiency Virus (HIV) and David decides to be tested. Blood samples are sent to a laboratory for an HIV g p 120 antibody/p 24 antigen test. The initial HIV results comes back as negative. However, David’s doctor decides to order another HIV test a week later and it comes back positive. QUESTION: INTERPRETING NEGATIVE TEST RESULTS This content was retrieved from Section 01, Slide 16 of 18 of the online learning module. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 19 MODULE 04 COMPANION GUIDE MICR 270 Answer the question using your working understanding of immunology. Why was the initial p 24/g p120 antibody/antigen HIV test negative? Review the answer. Feedback: The HIV antibody/antigen test relies on detecting the p 24 protein of HIV that may not be present at sufficient quantities in David’s blood within a week of infection. The test also tests for an antibody against the HIV g p 120 protein, the early negative test suggests that David had not mounted a sufficiently specific HIV g p 120 Ig G response for the test to detect. The HIV g p 120/p 24 antigen test has a “9-14 day window period” meaning that the test may not always work if HIV has been acquired in the last 9-14 days - so David’s doctor knowing this decided to wait a week and then re-test David for HIV. ACTIVITY: DIAGNOSIS This content was retrieved from Section 01, Slide 17 of 18 of the online learning module. Choose the correct answer based on the case study you just read. Which specific immune cell does HIV preferentially replicate in? 1. Cytotoxic T-cells 2. Helper T-cells 3. Natural Killer cells 4. Macrophages Feedback: Helper T-cells QUESTION: EXPLAINING THE IMMUNE RESPONSE This content was retrieved from Section 01, Slide 18 of 18 of the online learning module. Answer the following question based on the case study you just read. What response does David’s immune system exhibit following HIV infection? Review answer Feedback: In the first few weeks after infection with HIV, the level of CD4+ helper T-cells dramatically decreases, while the level of HIV in David’s blood increases. Humoral and cell-mediated immune responses are mounted and the level of CD4+ T-cells dips slightly. David’s body begins to produce antibodies and HIV-specific immune T cells (CTL) against the HIV virus, however the virus mutates, and continually evades the immune response. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 20 MODULE 04 COMPANION GUIDE MICR 270 While HIV continues to multiply at low levels over a long period of time, the level of CD4+ helper T-cells continually decrease. Ultimately David’s CD4+ T-helper cell count falls below 200 cells/m m3, David is clinically diagnosed as having an Acquired Immuno-Deficiency Syndrome (AIDS) and his risk of contracting opportunistic infections including Kaposi’s Sarcoma, CMV retinitis, and tuberculosis disease all increase substantially. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 21 MODULE 04 COMPANION GUIDE MICR 270 SECTION 02: AUTOIMMUNITY AUTOIMMUNITY This content was retrieved from Section 02, Slide 1 of 13 of the online learning module. As you may remember from Module 1, self-recognition is a necessary process of the immune system and allows the body to regulate and maintain a healthy immune system. The body must be capable of recognizing its own healthy cells, as well as infected/abnormal cells that may be harmful, and subsequently destroy them. In contrast to immunodeficiency where the immune system is weakened, in the case of autoimmunity the immune system is overactivated and attacks healthy cells and tissues. Learn more about the terms autoimmunity and autoimmune disease. Autoimmunity In some circumstances, the immune system initiates a reaction in response to its own cells. This reaction to self is what is called autoimmunity. Autoimmune Failure of an organism to distinguish self from nonself causes the immune system to initiate a response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease. BY THE NUMBERS This content was retrieved from Section 02, Slide 2 of 13 of the online learning module. There are more than eighty different kinds of autoimmune diseases, but what is the prevalence of these diseases in the general population? Learn about the statistics of autoimmune disease. Within the General Population Autoimmune diseases affect 5-7% of the human population. Within the Affected Population Autoimmune diseases more commonly affect females than males. Approximately 78% of individuals infected with an autoimmune disease are women. What is the main cause of autoimmune disease? The development of an autoimmune disease is highly dependent on genetics, but many other factors, such as infection by bacteria and/or viruses or chemical exposure, can play a role in their development. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 22 MODULE 04 COMPANION GUIDE MICR 270 CLASSIFICATION OF AUTOIMMUNE DISEASES This content was retrieved from Section 02, Slide 3 of 13 of the online learning module. Autoimmune diseases can be classified into two main categories: organ-specific or systemic. Autoimmune diseases often involve autoantibodies. An autoantibody is an antibody produced by the immune system that is directed against a self antigen. Learn about characteristics and examples of autoimmune diseases from these two categories. Organ-Specific Autoimmune Diseases Organ-specific autoimmune diseases involve an immune response that is directed to an antigen that is unique to a single organ or gland. As a result, the disease manifestations are largely limited to the specific organ. TARGET ORGANS The most common organs of the body affected by autoimmune disease are: Thyroid gland Stomach Adrenal glands Pancreas EXAMPLE OF AN ORGAN-SPECIFIC AUTOIMMUNE DISEASE Graves disease is an autoimmune disease that frequently leads to overactivity of the thyroid gland, known as hyperthyroidism. Learn more about this disease - Refer to pages 23-24 Systemic Autoimmune Disease In a systemic autoimmune disease, the immune response is directed towards a broad range of antigens that are characteristic of a number of organs and tissues. EXAMPLE OF A SYSTEMIC AUTOIMMUNE DISEASE Rheumatoid arthritis is a common autoimmune disorder that typically presents as chronic inflammation of joints, however other organ systems can also be affected. Learn more about this disease - Refer to page 24 GRAVES DISEASE Subpage of Section 02, Slide 3 of 13 – Learn more about this disease 1/2 Normal TSH Function INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 23 MODULE 04 COMPANION GUIDE MICR 270 Thyroid-stimulating hormone (TSH) is produced by the pituitary gland* and is crucial for regulating the production of thyroid hormones. Binding of TSH by receptors on thyroid cells stimulates the production of thyroid hormones, which control many aspects of metabolism. Negative feedback by thyroid hormones allows TSH production from the pituitary gland to be moderated. The Case of Graves Disease Patients with Graves disease produce autoantibodies to the receptor for TSH. These autoantibodies continuously engage TSH receptors but, unlike TSH, cannot be moderated. This results in an unregulated overproduction of thyroid hormones, leading to metabolic dysfunction. Definition*: Pituitary glad: The pea-sized major endocrine gland, found attached to the base of the brain, which is the source of trophic hormones that regulate growth, metabolism, and regulation and responds to feedback. CAUSE AND SYMPTOMS OF GRAVES DISEASE Subpage of Section 02, Slide 3 of 13 – Learn more about this disease 2/2 The exact cause of Graves disease is unknown but is thought to be a result of both genetic and environmental factors. Overstimulation of thyroid cells can lead to an enlargement of the thyroid gland, a condition referred to as a goiter. The metabolic dysfunction caused by Graves disease can result in weight loss, rapid heartbeat, poor regulation of body temperature, muscle weakness, and irritability. The goiter is an enlarged thyroid gland commonly observed in patients with Graves disease. RHEUMATOID ARTHRITIS Subpage of Section 02, Slide 3 of 13 – Learn more about this disease 1/1 It is most commonly observed in women aged 40 to 60. Many patients with rheumatoid arthritis produce autoantibodies, most commonly IgM, to portions of the Fc receptor of IgG, which are referred to as rheumatoid factors. Rheumatoid factors bind to circulating IgG forming immune complexes that become deposited within joints. These deposits can activate the complement cascade leading to prolonged inflammation and, ultimately, joint tissue damage. QUESTION: HOW CAN WE CURE OR TREAT AUTOIMMUNITY? This content was retrieved from Section 02, Slide 4 of 13 of the online learning module. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 24 MODULE 04 COMPANION GUIDE MICR 270 Answer the reflection question to the best of your knowledge. How do you think autoimmunity can be cured and/or treated? Feedback: Unfortunately, there is no cure for autoimmunity. Many diseases are still under investigation and researchers are trying to find better solutions. For now, we can only treat and try to reduce the reactions which is done by immunosuppression, but it also generates many unfortunate secondary effects. Proceed to the next slides to learn more about why and how this happens. TREATMENT OF AUTOIMMUNE DISEASES This content was retrieved from Section 02, Slide 5 of 13 of the online learning module. Unfortunately, there is no cure for autoimmune diseases. However, most autoimmune diseases are not as life-threatening as they were many years ago. Scientists have developed treatment methods that enable individuals with an autoimmune disease to live relatively normal lives. These therapies aim to reduce the symptoms of autoimmune diseases and provide patients with an improved quality of life. Immunosuppression Autoimmune diseases are typically treated using a class of drugs, called immunosuppressants. How does it work? As discussed throughout this section, the immune system is overactive in individuals with autoimmune diseases and has begun to attack the body tissues. These drugs suppress or reduce the strength of the body’s immune response. In an ideal world, treatment of autoimmune diseases would involve reducing only the erroneous autoimmune response while leaving the rest of the immune system intact. However, scientists have yet to discover a way in which this can be accomplished. IMMUNOSUPPRESSANTS AND ORGAN TRANSPLANTS This content was retrieved from Section 02, Slide 6 of 13 of the online learning module. In addition to treating autoimmune diseases, immunosuppressant drugs are commonly administered to individuals who have undergone an organ transplant. After transplantation the body recognizes the new organ as a foreign object and the immune system will initiate a response against it. Immunosuppressant drugs are therefore used to reduce the risk of rejection by inhibiting the immune response and allowing the organ to remain healthy in its new environment. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 25 MODULE 04 COMPANION GUIDE MICR 270 Because of their compromised immune system, it’s important individuals on immunosuppressants remain healthy and avoid infection - as their immune system may not be capable of fighting off foreign microbes. VIDEO: CLINICAL FOCUS ON ORGAN TRANSPLANTS This content was retrieved from Section 02, Slide 7 of 13 of the online learning module. Dr. Shamseddin is a Kidney Transplant Nephrologist and Medical Director of the Transplant Program at Queen’s University. Listen to Dr. Shamseddin explain why immunosuppression is so important during organ transplants. Focus on the principles of organ transplants and the processes of immunosuppression in a general fashion. This is a fascinating, yet complex, area of immunology; you are not responsible for knowing the drug names or the additional molecular pathways and details mentioned by Dr. Shamseddin that weren’t previously discussed in the module. These prompts will assist you in reviewing concepts discussed by Dr. Shamseddin that have already been explored in this course: 1. What are key characteristics of inflammation? 2. How is inflammation helpful? 3. How is inflammation harmful? 4. What steps are involved in activating T-cells? Page Link: https://player.vimeo.com/video/291512237 CLASSES OF IMMUNOSUPPRESSIVE DRUGS This content was retrieved from Section 02, Slide 8 of 13 of the online learning module. There are four main classes of immunosuppressive drugs, each of which target different points of the immune response. Although the names of drugs are provided, you will not be tested on them. Learn more about each class of immunosuppressive drug by going through the table. Class Action Example Corticosteroids Anti-inflammatory; Names: Prednisone kills T-cells Clinical Use: Provides relief for inflamed areas of the body. Cytotoxic Drugs Blocks cell division Names: Cyclophosphamide, methotrexate non-specifically Clinical Use: Treats cancer by slowing or stopping INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 26 MODULE 04 COMPANION GUIDE MICR 270 cell growth. Immunophilins Blocks T-cell Names: Cyclosporine responses Clinical Use: Used to prevent rejection in those receiving a transplanted organ. Lymphocyte-depleting Kills T-cells non- Name: Monoclonal antibodies Therapies specifically, kills Clinical Use: Used to prevent acute rejection in activated T-cells organ transplantation. ACTIVITY: MECHANISM OF IMMUNOSUPPRESSIVE DRUGS This content was retrieved from Section 02, Slide 9 of 13 of the online learning module. Based on what you learned from the previous slide, select the immunosuppressive drug that would be best suited to block each pathway. Options: Corticosteroid, Cytotoxic Drugs, Immunophilin, Lymphocyte-depleting Therapy Feedback: Left row (from left to right): Corticosteroid, Immunophilin Right column (from top to bottom): Lymphocyte-depleting Therapy, Cytotoxic Drugs THE DOWNSIDES TO IMMUNOSUPPRESSIVE DRUGS This content was retrieved from Section 02, Slide 10 of 13 of the online learning module. Although immunosuppressive drugs are beneficial to use in certain medical instances, they also have their drawbacks. As with any other drugs, each immunosuppressive drug class has potential side effects. Immunophilin Drug: Cyclosporine Possible Side Effects: Nephrotoxicity, hypertension, hirsutism, hypertrichosis, gingival hyperplasia Cytotoxic Drugs Drug: Cyclophosphamide Possible Side Effects: nausea, vomiting, loss of appetite, stomach ache, diarrhea, darkening of skin/nails Drug: Methotrexate Possible Side Effects: nausea, vomiting, hair loss, tiredness, dizziness, chills headache, mouth sores, sores in lungs, increased risk of skin infection, sun sensitivity, rash, stuffy or runny nose and sore throat, low blood cell levels Corticosteroids INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 27 MODULE 04 COMPANION GUIDE MICR 270 Drug: Prednisone Possible Side Effects: Osteoporosis, hirsutism, hypertrichosis, diabetogenic IMPACT OF IMMUNOSUPPRESSION ON THE HOST This content was retrieved from Section 02, Slide 11 of 13 of the online learning module. In addition to the potential side effects that each class of immunosuppressive drugs can cause, some patients may develop latent or opportunistic infections. These infections tend to develop because of the host’s weakened immune system. Latent Infections Individuals that are on immunosuppressive therapy have an increased risk of reactivation of pathogens that are usually associated with latent infections*. The most common pathogens include: TB*, HSV 1/2*, CMV*, EBV*, and VZV*. Opportunistic Infections Opportunistic infections commonly occur when there is reactivation of a pathogen that is already present in the host. These infections can also result when a pathogen is picked up from the environment, but the blunted immune response of the host is unable to combat the pathogen. Opportunistic infections can arise from bacteria, viruses, parasites or fungi. Definitions*: Latent infections: Infections that are inactive, hidden, or dormant. TB: Tuberculosis HSV1/2: Herpes Simplex ½ CMV: Cytomegalovirus EBV: Epstein–Barr Virus VZV: Varicella Zoster Virus OPPORTUNISTIC INFECTIONS This content was retrieved from Section 02, Slide 12 of 13 of the online learning module. Fungal Name: Pneumocystis Jiroveci Pneumonia Common Name: PCP Infects: Pneumonia of lungs Name: Cryptococcosis Common Name: Cryptococcal disease INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 28 MODULE 04 COMPANION GUIDE MICR 270 Infects: Lungs, which may spread to brain Name: Candidiasis Common Name: Thrush Infects: Mouth, throat, and vagina Name: Aspergillosis Common Name: N/A Infects: Lungs Parasitic Name: Toxoplasmosis Common Name: N/A Infects: Skeletal muscle, myocardium, brain, and eyes Bacterial Name: Tuberculosis Common Name: Consumption Infects: Lungs Name: Mycobacterium Avium Complex Common Name: MAC Infects: Lungs, lymph nodes, or entire body depending on site of infection Viral Name: Cytomegalovirus Common Name: CMV Infects: Eyes, brain, or other internal organs Name: Herpes Simplex Virus (HSV) Common Name: Herpes Infects: Skin, mouth, lips, eyes, and genitals THE IMPACT OF IMMUNOSUPPRESSIVE DRUGS This content was retrieved from Section 02, Slide 13 of 13 of the online learning module. The use of immunosuppressive drugs is a necessity in specific circumstances. Based on what you have just learner, it is evident that immunosuppressive drugs offer advantages to medical treatments, but they also have inherent side effects. In today’s medical world, with organ transplants increasingly becoming the future of medical care, immunosuppressive drugs have an instrumental role to play. When physicians use these drugs, and other drugs in general, they always have to weigh out the benefits and risks, to be able to decide what is best for their patients. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 29 MODULE 04 COMPANION GUIDE MICR 270 Now you can appreciate that ultimately, immunosuppressive therapies are good, however they need to be used cautiously. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 30 MODULE 04 COMPANION GUIDE MICR 270 SECTION 03: HYPERSENSITIVITY CLASSIFICATION OF HYPERSENSITIVITIES This content was retrieved from Section 03, Slide 1 of 19 of the online learning module. Hypersensitivity refers to excessive reactions produced by the normal immune system. Clinical conditions vary based on the mechanisms involved and time taken for the reaction to develop. Review the table for an overview of each type of hypersensitivity. You will learn more about each throughout this section. Type I Type II Type III Type IV Other name Immediate/Anaphylaxis Cytotoxic Immune complex- Delayed-type mediated Common Allergic reactions Blood diseases: Contribute to Skin reactions examples Food allergies Transfusion development of Contact Reactions autoimmune dermatitis Hemolytic diseases: disease of Systemic lupus the erythematosus newborn Rheumatoid arthritis TYPE I HYPERSENSITIVITY This content was retrieved from Section 03, Slide 2 of 19 of the online learning module. Type I hypersensitivity is also known as immediate or anaphylactic hypersensitivity. Learn about the characteristics of type I hypersensitivity Mediators Key players in type I hypersensitivity include: IgE Basophils Mast cells Allergens Normally a harmless substance, an allergen produces an abnormal immune response called allergic reaction in certain individuals. In humans there are 8 major food allergens. Milk Eggs Fish Crustacean Shellfish INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 31 MODULE 04 COMPANION GUIDE MICR 270 Tree Nuts, Peanuts Wheat, Soya. Mechanism of Reaction Primary exposure to an allergen: The allergen induces a humoral immune response wherein plasma cells secrete an excessive amount of IgE antibodies which bind to mast cells and basophils. Secondary exposure to the same allergen: Membrane-bound IgE cross-links with the allergen which initiates the degranulation* of basophils and mast cells, releasing vasoactive mediators causing vasodilation and smooth muscle contraction. Reaction Time Type I hypersensitivity reaction can be immediate (minutes – anaphylactic reactions) and can lead to death in as little as 15 fifteen minutes. Rare type 1 reactions can take longer (developing after 24 hours,) but most occur soon after exposure. Clinical Manifestation Type I hypersensitivity reaction clinical manifestations include: Allergic rhinitis: A generalized irritation of the nose when the immune system overreacts to allergens in the air. Asthma: A respiratory condition in which the airways narrow, swell, and produce extra mucus. Atopic dermatitis (eczema): A condition where an individual develops skin eruptions accompanied by redness. Hives (urticaria): A rash of itchy round, red welts on the skin that may also burn, sting, or swell. The risks of an anaphylactic shock. Watch a short segment about the risks of anaphylaxis. Definition*: Degranulation: Release of granules. Page Link: INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 32 MODULE 04 COMPANION GUIDE MICR 270 https://www.youtube.com/embed/TTcL7u05aUU TYPE II HYPERSENSITIVITY This content was retrieved from Section 03, Slide 3 of 19 of the online learning module. Type II hypersensitivity is also known as antibody-mediated cytotoxic hypersensitivity. Learn about the characteristics of type II hypersensitivity. Mediators Key players in type II hypersensitivity include: IgG IgM NK Cells The Complement System Mechanism of Reaction IgGs and/or IgMs bind to antigens on the surface of cells such as erythrocytes (e.g. following a blood transfusion - ABO blood-group incompatibility). Once the antibodies are attached to the cell through their antigen-binding region, the Fc region is free and can activate two processes called classical complement activation (leading to opsonization* or membrane attack complexes*) and antibody-dependent cell-mediated cytotoxicity (ADCC). The mechanisms will not be covered in detail in this course, but you should know that the activation of these processes mediate the destruction of the cells, leading to an excessive inflammatory response. Reaction Time The reaction time of a type II hypersensitivity reaction is minutes to hours. Clinical Manifestation Type II hypersensitivity reaction clinical manifestations include: Drug-induced hemolytic anemia: Some antibiotics can bind nonspecifically to proteins on RBC* membranes and form a complex which sometimes induces complement-mediated lysis. As the RBCs rupture, the number of RBCs decrease resulting in anemia. Anemia* disappears when the drug is removed. Penicillin is notable in inducing hemolytic anemia. Transfusion reactions: Depending on your blood type, you will only be able to safely receive certain blood types during a blood transfusion. This is partly due to the presence or absence of expression of a specific antigen (A or B) on your RBCs; meaning if you don’t express the antigens, you have antibodies against them. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 33 MODULE 04 COMPANION GUIDE MICR 270 Who is a universal donor? A person with an O negative blood type is considered a universal donor as they can give blood to all other blood types (as they do not have A or B antigens on the surface of their RBCs). On the other hand, a person with an AB positive blood type is considered a universal recipient as they can receive blood from all the other blood types (as they will not have antibodies against A or B antigens). Definitions*: MAC: Recall that the membrane attack complex (MAC) creates holes in the cell membrane leading to cell lysis. Opsonization: Recall that opposition leads to phagocytosis by phagocytes such as macrophages. RBC: Red blood cell or erythrocyte. Anemia: A condition characterized by a deficiency of red blood cells or hemoglobin in the blood. TYPE III HYPERSENSITIVITY This content was retrieved from Section 03, Slide 4 of 19 of the online learning module. Type III hypersensitivity is also known as immune-complex mediated hypersensitivity. Learn about the characteristics of type III hypersensitivity. Mediators Key players in type III hypersensitivity include: Immune complexes: Antigen-antibody complexes Neutrophils Complement proteins Mechanism of Reaction The reaction of antibodies with antigens generates immune complexes. When immune complexes are not cleared, they can accumulate and deposit in the tissue. These immune complexes will activate the complement which will induce inflammatory reactions through neutrophil attraction to the site of deposition. Neutrophils release lytic enzymes as they attempt to phagocytose the immune complexes, which weakens surrounding cell membranes ultimately causing tissue damage. Reaction Time The reaction of a type III hypersensitivity may take 3 to 10 hours after exposure to the antigen. Sometimes the reaction can take longer to develop (days to weeks). INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 34 MODULE 04 COMPANION GUIDE MICR 270 Clinical Manifestation A type III hypersensitivity reaction clinical manifestation includes: Serum sickness: These reactions are often observed after administration of antitoxins* containing foreign serum. The recipient of these antiserums* develop antibodies specific for this protein. When these antibodies circulate, they form immune complexes with the protein. After a couple of days to a week, the symptoms of serum sickness occur, including fever, weakness, and generalized vasculitis (rashes) with edema. Often complexes accumulate in tissues where filtration of plasma occur and can contribute to the pathogenesis of many other conditions such as autoimmune diseases (e.g. arthritis), hepatitis, and malaria. Clinical effects will subside when the antigen has been completely broken down. A person with an O negative blood type is considered a universal donor as they can give blood to all other blood types (as they do not have A or B antigens on the surface of their RBCs). On the other hand, a person with an AB positive blood type is considered a universal recipient as they can receive blood from all the other blood types (as they will not have antibodies against A or B antigens). Definitions*: Antitoxins: An antibody that counteracts a toxin. Antiserums: Blood serum containing antibodies against specific antigens, injected to treat or protect against specific diseases. TYPE IV HYPERSENSITIVITY This content was retrieved from Section 03, Slide 5 of 19 of the online learning module. Type IV hypersensitivity is also known as cell-mediated or delayed-type hypersensitivity (D T H). Learn about the characteristics of type IV hypersensitivity. Mediators Key players in type IV hypersensitivity include: CD8+ Cytotoxic T-cells CD4+ Helper T-cells Macrophages Note: Unlike other types of hypersensitivity, type IV hypersensitivity is not mediated by antibodies. Mechanism of Reaction INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 35 MODULE 04 COMPANION GUIDE MICR 270 After exposure to an antigen, T-cells will become activated and initiate an immune response. Sensitized helper T-cells (specifically TH1) will release cytokines that activate macrophages or cytotoxic T-cells which mediate direct cellular damage. Reaction Time The reaction of a type IV hypersensitivity has a delayed response and can take two to three days to develop after exposure to a particular substance. Clinical Manifestation Type IV hypersensitivity reaction clinical manifestations include: Inflammatory Bowel Disease (IBD): IBD is a group of conditions that is characterized by chronic inflammation of all or parts of the digestive tract. The two most common diseases are: Ulcerative colitis Crohn’s disease IBD falls into the class of autoimmune disease - where the immune system attacks the body’s own cells. Contact Dermatitis: Contact dermatitis is a type of DTH response causing a red itchy rash on the skin that has been in contact with small, reactive molecules which create complexes with skin proteins. Common inducers of contact dermatitis include: poison ivy, formaldehyde, nickel and cosmetics. HYPERSENSITIVITY - PATIENT CASE #1 This content was retrieved from Section 03, Slide 6 of 19 of the online learning module. Examine this case study that demonstrates a characteristic diagnosis, clinical history, and examination of a hypersensitivity reaction. While you read through the case study, think about the mediators and the type of immune response that could be responsible for the symptoms described. Victor, a 21-year-old college student living at his school dormitory, comes to his family physician with a complaint of stomach cramps and blood in his stool. Review each stage of examination to learn more about Victor’s diagnosis. Review of Symptoms 6 months ago INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 36 MODULE 04 COMPANION GUIDE MICR 270 Onset of abdominal pain around his navel o Quite evident right after a large meal o Sometimes associated with vomiting o Accompanied by joint stiffness and some pain in his hands, wrists, hips, and ankles 3 months ago Relapsing pain Unusually tired On several occasions was feverish (not associated with symptoms of a cold) 4 weeks ago Noticed that his stool was looser, more frequent and sometimes bloody. Examination Victor looks fairly well Underweight for his age Abdomen: o Tender, especially on the right side o No palpable mass o No liver or spleen enlargement Oral Mucosa: o Three ulcers noted Joints: o No sign of synovitis* or loss of motion Rectal: o No evidence of any abnormality List of Tests Performed Based on the patient’s history and the presence of specific symptoms, the physician orders: Ova/Parasite investigation and stool culture o To search for parasites Complete Blood Count (CBC) o To evaluate the overall health and detect a wide range of disorders Erythrocyte sedimentation rate (ESR)* o Rate at which red blood cells sediment in one hour o A non-specific measure of inflammation C-reactive protein levels* o A protein produced by the liver INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 37 MODULE 04 COMPANION GUIDE MICR 270 o Blood test marker for inflammation in the body Definitions*: Synovitis: Inflammation of a synovial membrane, which is a component of the synovial joint (the most movable joints in the human body) that attaches bones with a fibrous joint capsule. Erythrocyte sedimentation rate (ESR): The rate at which red blood cells sediment in one-hour. ESR is useful diagnostic test is used as marker of inflammation and can help confirm the presence of a variety of disease states. Inflammation can cause red blood cells to clump and the more inflammation that is present, causes more cells to clump and sediment which is detected as a higher ESR. C-reactive protein levels: A marker of inflammation in the body. C R P is a more accurate reflection of the acute phase immune response (early induced innate immunity) than ESR. More inflammation present in the body is reflected by increased levels of C R P. HYPERSENSITIVITY - PATIENT CASE #1 TEST RESULTS This content was retrieved from Section 03, Slide 7 of 19 of the online learning module. Learn the results of each test performed. Microscopic Examination and Culture of Stool Specimen Presence of white blood cells (WBCs) No parasites or enteric bacteria Complete Blood Count Mildly elevated for white blood count Microcytic anemia* Erythrocyte Sedimentation Rate Elevated C-Reactive Protein Levels Elevated Test Conclusions All indicators of inflammation, but no indicator of infection. Definition*: Microcytic anemia: Presence of small red blood cells. QUESTION: HYPERSENSITIVITY (1) INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 38 MODULE 04 COMPANION GUIDE MICR 270 This content was retrieved from Section 03, Slide 8 of 19 of the online learning module. Answer the following question based on the case study you just read. Based on everything you just learned and the list of symptoms and test results, what type of hypersensitivity could the diagnosis be? Feedback: The physician suspects that Victor may have a form of inflammatory bowel disease, such as Crohn’s Disease or Ulcerative Colitis (Type IV hypersensitivity). QUESTION: HYPERSENSITIVITY (2) This content was retrieved from Section 03, Slide 9 of 19 of the online learning module. Based on the findings of the medical examination, the physician sends Victor to a gastroenterologist for a diagnostic work up. The gastroenterologist reviews Victor’s medical history, laboratory findings, and performs another physical examination. He also comes to the conclusion that Victor likely has an inflammatory bowel disease and sends Victor for a colonoscopy*. Answer the following question about Victor’s condition. If Victor does have IBD, what could the colonoscopy reveal? Feedback: Inflammation and ulceration in the rectum and colon. Definition*: Colonoscopy: A procedure in which a flexible fiber-optic instrument is inserted through the anus in order to examine the colon. HYPERSENSITIVITY - PATIENT CASE #1 DIAGNOSIS This content was retrieved from Section 03, Slide 10 of 19 of the online learning module. The procedure reveals inflammation marked by the presence of ulceration in the rectum and colon. It also reveals multiple lacerations reaching from the caecum of the large intestine to the ileum of the small intestine. Biopsies are taken from the inflamed areas and upon histologic examination, the presence of severe infiltration of mucosa with mononuclear cells is observed. The endoscopic and histological findings are both fully suggestive of Crohn’s disease, rather than ulcerative colitis. QUESTION: HYPERSENSITIVITY (3) This content was retrieved from Section 03, Slide 11 of 19 of the online learning module. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 39 MODULE 04 COMPANION GUIDE MICR 270 Answer the following question based on the case study you just read and what you have learned in this course. Is irritable bowel disease mediated by immunoglobulins? o True o False Feedback: False Remember, IBD is an example of Type IV hypersensitivity. This type of hypersensitivity is the only type of hypersensitivity discussed that does not involve antibodies; it is cell-mediated. QUESTION: PATIENT CASE #1 EXPLAINING THE IMMUNE RESPONSE This content was retrieved from Section 03, Slide 12 of 19 of the online learning module. Answer the following question based on the case study you just read and what you have learned in this course. What is the immune response with respect to IBD? How does this response result in the symptoms associated with IBD? Feedback: After exposure to an antigen, T-cells become activated and initiate the immune response. Helper T-cells will release cytokines which cause cellular damage. Helper T-cells then activate cytotoxic T-cells, which can cause direct cellular damage to the bowel and colons, causing inflammation and discomfort. This inflammation can cause blood in the stool and abdominal pain. HYPERSENSITIVITY - PATIENT CASE #2 INTRODUCTION This content was retrieved from Section 03, Slide 13 of 19 of the online learning module. Examine the following case study that demonstrates a characteristic diagnosis, clinical history, and examination of a hypersensitivity reaction. While you read through the case study, think about the mediators and the type of immune response that could be responsible for the symptoms described. John, an 8 year old boy who is actively wheezing, arrives at the doctor’s office with his parents. His father explains that there has been two episodes of breathing difficulty and wheezing in the last two weeks. John did not respond to his albuterol* inhaler. In addition to albuterol, he is on a corticosteroid inhaler and antihistamine to stop his runny nose. John does not have a fever, shakes, or chills, but complains of a chronic cough, especially in the morning, at night, and when running. Definition*: Albuterol: Albuterol is used to relax muscles found in the airways to increase airflow to the lungs. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 40 MODULE 04 COMPANION GUIDE MICR 270 HYPERSENSITIVITY - PATIENT CASE # 2 MEDICAL HISTORY This content was retrieved from Section 03, Slide 14 of 19 of the online learning module. Use the timeline to learn about John’s medical history, which will help you make your diagnosis. Birth to 3 years old John was born with a birth weight of 7 l b 3 o z with excellent AGPAR* scores. He achieved developmental milestones on time. As an infant he had frequent skin rashes (eczema/atopic dermatitis), which were managed by over-the-counter medications. 3 Years Old At age 3, the first episode of wheezing occurred, preceded by an upper respiratory tract viral infection. 4 Years Old At age 4, these episodes became more frequent, occurring 4-5 times a year, particularly during spring. These episodes were generally responsive to the albuterol inhaler at home. However, one episode required a visit to the emergency room with a short course of oral steroids added to the albuterol. The wheezing attacks John experienced were often associated with cough, fever, headache, and nasal discharge containing pus, white blood cells, and bacteria. At these times, John was diagnosed with a secondary bacterial infection and was treated with oral antibiotics. Since 5 Years Old In addition, since age 5, John had intermittent sneezing episodes associated with clear nasal discharge. Definition*: AGPAR: An AGPAR score is a method to quickly summarize the health of a newborn child. The AGPAR score is determined by evaluating the newborn baby on five criteria, Appearance, Pulse, Grimace, Activity and Respiration on a scale from zero to two. The five values are then summed to give the AGPAR score. A score of 7 and above is considered normal. HYPERSENSITIVITY - PATIENT CASE #2 SOCIAL AND FAMILY HISTORY This content was retrieved from Section 03, Slide 15 of 19 of the online learning module. Consider the following information with respect to John’s social and family history in your evaluation of this case study. Social and family histories are often linked to certain disease states and can predispose individuals to many diseases. Learn more about John and John’s family situation. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 41 MODULE 04 COMPANION GUIDE MICR 270 Familial Situation The patient lives with his mother, father, and younger sister who is 9 months old. Family Members Medical History Sister has recently been diagnosed with eczema and father had history of asthma as a child. Activities and Physical Condition John enjoys playing sports including soccer, but gets frustrated trying to keep up with his friends. HYPERSENSITIVITY - PATIENT CASE #2 PHYSICAL EXAMINATION This content was retrieved from Section 03, Slide 16 of 19 of the online learning module. Evaluate the following results from John’s physical examination and consider how they result from an immune reaction. ✓ Marked respiratory distress with easily audible wheezing ✓ Respiratory rate 40 breaths/minute (normal 18-30 breaths/min) ✓ Heart rate 100 beats/min (normal 70-80 beats/min) ✓ John has congested swollen sinuses with infected discharge from both nasal passages ✓ His throat is mildly red and has mild lymph node enlargement in the neck ✓ Rest of the examination is normal HYPERSENSITIVITY - PATIENT CASE #2 DIAGNOSIS This content was retrieved from Section 03, Slide 17 of 19 of the online learning module. Learn about John’s diagnosis and how his condition and his symptoms are linked. What is John’s diagnosis? John’s diagnosis is asthma. Asthma is defined as an abnormal inflammatory response to a specific or nonspecific stimuli in the bronchial lining, resulting in obstruction of small and large airways. During an asthma attack the muscles in the airway contract and the walls become inflamed, resulting in a narrow airway with thickened walls - as shown in the image. There is also an increase in mucus secretion during this time, further impeding the patient's airway. Asthma can’t be cured, but it can be managed. With proper treatment, people with asthma can lead normal, active lives. HYPERSENSITIVITY - PATIENT CASE #2 This content was retrieved from Section 03, Slide 18 of 19 of the online learning module. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 42 MODULE 04 COMPANION GUIDE MICR 270 Answer the following question about the case study you have just read using what you have learned so far in the course. What is the immunoglobulin responsible for the overreaction of John’s immune system? o IgA o IgD o IgE o IgG o IgM Feedback: The immunoglobulin IgE is responsible for John’s overactive immune response because John suffers from Type I or anaphylactic hypersensitivity. This type of hypersensitivity is mediated by the cross-linking of membrane bound IgE with an allergen facilitating the degranulation of these cells. QUESTION: PATIENT CASE #2 EXPLAINIG THE IMMUNE RESPONSE This content was retrieved from Section 03, Slide 19 of 19 of the online learning module. Answer the following question about the case study you just read. Using what you learned about Type I Hypersensitivity, explain the immune response responsible for the asthma that is seen in John's case. Review answer Feedback: Allergic inflammation develops from an interplay between immune cells and respiratory epithelium. The environmental or inflammatory stimuli induce a humoral antibody response. B-cells differentiate into plasma cells and enter the lungs where they begin to produce and secrete an excess amount of IgE. Upon a secondary exposure to the same stimuli, the memory of B-cell recognize the stimuli and initiate a quick immune response. The membrane-bound IgE on the surface of mast cells with then cross-link, causing degranulation. The granules will induce vasodilation and smooth muscle contraction, which cause the difficulty breathing associated with asthma. INFECTION, IMMUNITY, AND INFLAMMATION | MICR 270 M04 PAGE 43 MODULE 04 COMPANION GUIDE MICR 270 CONCLUSION MODULE SUMMARY This content was retrieved from Conclusion, Slide 1 of 5 of the online learning module. After working through the previous three modules, you’ve hopefully come to appreciate that your immune system is an intricately regulated network of many different cell types functioning cooperatively to avoid attacking self and protect you from non-self antigens. Given this complexity, there are many different instances, during the development and training of the immune system, at which errors may be made in one or more of the immune response processes. This module provides you with some examples and current classification of immune system malfunctions along with the associated human disease conditions. CONCEPT MAP: LIST OF IMMUNOLOGY TERMINOLOGY This content was retrieved from Conclusion, Slide 2 of 5 of the online learning module. After completing Module 4, you should be able to include some more words in your concept map review! The major concepts covered in this module are highlighted in the word list. Remember that this is a tool for you to use throughout the course. Legend: Component, Process, Organ, Cell Adaptive system Complement Immune response Memory cell Physical barrier Antibody Cytokine Immune synapse Monocyte Plasmocyte Antigen Cytotoxic T-cell Immunodeficiency Macrophage Spleen Antigen Dendritic cell Immunotherapy Natural Killer cell T-cell presentation Autoimmunity Damage- Inflammation Neutrophil Thymus Basophil Associated Innate system Pattern Toll-Like Molecular Recognition Receptor (TLR ) Pattern (DAMP) Receptor (PRR) B-cell Eosinophil Lymph node Bone marrow Helper T-cell Lymphatic system Pathogen- Vaccination Cancer Humoral Major Associated Histocompatibility Molecular Complex (MHC) Pattern (PAMP) Cell-mediated Hypersensitivity Phagocytosis LEARNING OUTCOMES This content was retrieved from Conclusion, Slide 3 of 5 of the online learning module. Now that you are at the end of Module 4, you should be able to: Compare and contrast primary and secondary immunodeficiencies. Hypothesiz

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