Immune System in Health and Disease PDF

The immune system in health and disease DR NANCY LAMBRIANIDES N E U R O I M M U N O L O G Y D E PA R T M E N T THE CYPRUS INSTITUTE OF NEUROLOGY AND GENETICS Lecture 23 contents: 1. Evasion of the immune system 2. Immunodeficiencies 3. Hypersensitivities Immune...

The immune system in health and disease DR NANCY LAMBRIANIDES N E U R O I M M U N O L O G Y D E PA R T M E N T THE CYPRUS INSTITUTE OF NEUROLOGY AND GENETICS Lecture 23 contents: 1. Evasion of the immune system 2. Immunodeficiencies 3. Hypersensitivities Immune system in health In a healthy individual, the immune system functions optimally, providing protection against infections, clearing out damaged cells, and maintaining overall wellness. Several factors contribute to a healthy immune system: 1. Balanced Nutrition: A diet rich in vitamins, minerals, and antioxidants supports immune function. 2. Adequate Sleep: Sufficient sleep is crucial for immune health, as it allows the body to recharge and repair. 3. Regular Exercise: Moderate physical activity boosts the immune system and reduces the risk of infections. 4. Stress Management: Chronic stress can weaken the immune system, so stress reduction techniques are important for maintaining immune health. Evasion of the immune defenses Antigenic variation allows pathogens to escape immunity - 3 main forms: 1. Many pathogens exist in a wide variety of antigenic types 2. Antigenic drift / antigenic shift 3. Programmed gene rearrangements Streptococcus pneumoniae differ in the structure of their polysaccharide capsules Antigenic drift /shift A series of spontaneous point mutations that generate minor antigenic variations in pathogens and lead to strain differences A sudden emergence of a new pathogen subtype resulting from genetic reassortment leading to substantial antigenic differences  Persistence and reactivation of infection Some viruses enter a state in which the virus is not being replicated – latency Latent infections can be reactivated e.g. herpesviruses (cold sores, shingles) Immune system in disease 1. Immunodeficiency Disorders: These occur when the immune system is weakened, making individuals more susceptible to infections. Examples include HIV/AIDS and primary immunodeficiency disorders. 2. Autoimmune Diseases: In these conditions, the immune system mistakenly attacks the body's own cells and tissues. Examples include rheumatoid arthritis, lupus, and type 1 diabetes. 3. Allergies: An overactive immune response to harmless substances characterizes allergies. The immune system reacts excessively, leading to symptoms like sneezing, itching, and inflammation. 4. Cancer: Some cancers evade the immune system's surveillance mechanisms, allowing them to grow and spread. Immunodeficiency diseases Primary immunodeficiencies: -caused by inherited mutations in genes that control immune responses -highly variable clinical features -overwhelming infections in young children Secondary immunodeficiencies: -are acquired as a consequence of other diseases -are secondary to environmental factors such as starvation or medical intervention Primary Immunodeficiencies Are classified by the main component of the immune system that is deficient, absent, or defective: - Humoral Immunity - Cellular Immunity - Combined humoral and cellular immunity - Phagocytic cells - Complement proteins Prevalence Individual type of primary immunodeficiencies (PIDs) are considered to be rare in the population; Recent studies have shown that PIDs may be more common than previously estimated, 1% of the population when all varieties are combined It is estimated that 70–90% of individuals living with a PID are undiagnosed, particularly in areas with poor medical conditions and lacking laboratory resources Humoral immunity deficiencies B-cell defects that cause antibody deficiencies account for 50 to 60% of primary immunodeficiencies. Serum antibody titers decrease, predisposing to bacterial infections. The most common B-cell disorder is Selective IgA deficiency Cellular immunity deficiencies T-cell defects account for about 5 to 10% of primary immunodeficiencies and predispose to infection by viruses, fungi, other opportunistic organisms, and many common pathogens). T-cell disorders also cause Ig deficiencies because the B- and T-cell immune systems are interdependent. The most common T-cell disorders are DiGeorge syndrome Zeta-associated protein 70 (ZAP-70) deficiency X-linked lymphoproliferative syndrome Chronic mucocutaneous candidiasis Primary natural killer cell defects, which are very rare, may predispose to viral infections and tumors. Secondary natural killer cell defects can occur in patients who have various other primary or secondary immunodeficiencies.  DiGeorge’s syndrome Thymic epithelium fails to delevop normally T cells cannot mature Both cell-mediated immunity and T-cell dependent antibody production are impaired Normal levels of serum Ig but absence of or incomplete development of thymus and parathymoid glands with varying degrees of T-cell immunodeficiency Combined humoral and cellular immunity deficiencies B- and T-cell defects account for about 20% of primary immunodeficiencies. The most important form is: Severe combined immunodeficiency (SCID) In some forms of combined immunodeficiency, Ig levels are normal or elevated, but because of inadequate T-cell function, antibody formation is impaired. Severe Combined Immunodeficiency (SCID) Infants that make neither T-cell dependent antibody responses nor cell-mediated immune responses and cannot develop immunological memory X-linked SCID more common, caused by mutations in the gene IL2RG on the human X chromosome, which encodes the interleukin-2 receptor common gamma chain Infants have prolonged diarrhea due to rotavirus or bacterial infection of the gastrointestinal tract and develop pneumonia Infants with SCID have very few lymphocytes in their blood The optimal treatment is bone-marrow transplant from a completely histocompatible donor, usually a normal sibling  Wiskott-Aldrich syndrome X-linked immunodeficiency disease Affected males have small and abnormal platelets – thrombocytopenia Develop severe eczema and opportunistic infections Their serum contains increased amounts of IgA and IgE, normal levels of IgG and decreased amounts of IgM Defective T-cells in function and malfunction of cell-mediated immunity gets worse Phagocytic cell defects Phagocytic cell defects account for 10 to 15% of primary immunodeficiencies; the ability of phagocytic cells (eg, monocytes, macrophages, granulocytes such as neutrophils and eosinophils) to kill pathogens is impaired. Cutaneous staphylococcal and gram-negative infections are characteristic. The most common (although still rare) phagocytic cell defects are Chronic granulomatous disease Leukocyte adhesion deficiency (types 1 and 2) Cyclic neutropenia Complement deficiencies Complement deficiencies are rare (≤ 2%); they include isolated deficiencies of complement components or inhibitors and may be hereditary or acquired). Hereditary deficiencies are autosomal recessive except for deficiencies of C1 inhibitor, which is autosomal dominant, and properdin, which is X-linked. The deficiencies result in defective opsonization, phagocytosis, and lysis of pathogens and in defective clearance of antigen- antibody complexes. The most serious consequences are Recurrent infection, which is due to defective opsonization Autoimmune disorders (eg, SLE, glomerulonephritis), which is due to defective clearance of antigen-antibody complexes A deficiency in a complement regulatory protein causes hereditary angioedema. Complement deficiencies can affect the classical and/or alternate pathways of the complement system. The alternate pathway shares C3 and C5 through C9 with the classical pathway but has additional components: factor D, factor B, properdin (P), and regulatory factors H and I. Secondary immunodeficiencies Extremely common and important in every day medical practice A major feature of malnutrition is secondary immunodeficiency- measles causes immunosuppression and a high mortality in malnourished children Also associated with tumors (leukemia and lymphomas) – metastases from other cancers can promote opportunistic infections One of the major side effects of cytotoxic drugs used to treat cancer Acquired immune deficiency syndrome (AIDS) The most extreme case of immune suppression – caused by infection with HIV HIV infection leads to gradual loss of immune competence The disease is characterized by susceptibility to infection with opportunistic pathogens or by the occurrence of an aggressive form of Kaposi’s sarcoma or B-cell lymphoma Hypersensitivity – Allergic reactions Classified into 4 types Type I hypersensitivity reactions are immediate-type allergic reactions initiated by IgE antibodies üallergies to food, üpollen, ühouse dust Other allergic reactions, such as serum sickness, allergic contact dermatitis and celiac disease do not involve IgE and are due to type II, III or IV hypersensitivity reactions Type I hypersensitivity reactions IgE mediated and involve mast-cell degranulation Binding of antigen to IgE cross-links the high affinity IgE receptor (FceRI), causing the release of chemical mediators from mast cells that can lead to allergic disease Factors that contribute to the development of IgE- mediated allergic disease Genetic: -e.g asthma susceptibility genes: involve genes triggering the immune response, directing CD4 TH cell differentiation and genes regulating TH2 cell differentiation Environmental: -Changes in exposure to infectious diseases in early childhood -The younger children of a family and children who are exposed to other children in daycare are protected against asthma -Other: changes in diet, allergen exposure, atmospheric pollution and tobacco smoke Effects of mast cell activation on different tissues Once mast cells are activated, they induce inflammatory reactions by secreting mediators (histamines) Also release cytokines and chemokines after activation Symptoms range from swollen eyes and rhinitis, eye conjuctivitis to anaphylaxis Allergen introduced into the bloodstream can cause anaphylaxis Symptoms of anaphylaxis range from mild urticaria to fatal anaphylactic shock Anaphylactic shock: increase in vascular permeability - loss of blood pressure, shock; airways constrict -difficulty in breathing and swelling of the epiglottis - suffocation Can usually be controlled by immediate injection of epinephrine Type II and Type III hypersensitivity reactions Hypersensitivity responses involving IgG antibodies  Type II hypersensitivity reactions Definition In type II, the target is fixed in tissue or on the cell surface. This is mediated by IgG binding to the specific cell or tissue. Damage will be limited to the tissue/cells where this reaction will take place. Antigen: It is present or is a part of the cell membrane. It may be: Exogenous Ag: Microbes, parasites, drugs. Intrinsic Ag: Autoimmune diseases, and these are self-Ag. Antibody: This is mainly due to IgG. Effector cells: macrophages, neutrophils, eosinophils, and NK (natural killer) cells. Mechanism Complement activation: ◦ The antibody attaches to antigen on the surface of cells and activates the complement system, which leads to lysis. Antibody-dependent cellular toxicity (ADCC): ◦ Sometimes Antibody is attached to Antigen on the cell surface will bring this complex near to NK cells or other phagocytic cells possessing the Fc-Receptor and leads to antibody dependant cellular cytotoxicity (ADCC). Opsonization and phagocytosis: ◦ The antibody binds to an antigen and makes it a target for phagocytosis, and this process is called opsonization. Type II hypersensitivity reactions examples: Antibody-mediated destruction of RBC (hemolytic anaemia) or platelets (thrombocytopenia) caused by some drugs (penicillin and cephalosporin)  Type III hypersensitivity reactions Definition: Type III hypersensitivity occurs when there is accumulation of antigen-antibody complexes that have not been cleared by innate immune cells, giving rise to an inflammatory response and attraction of leukocytes Mechanism: There are three steps that lead to this response: 1. The first step is immune complex formation, which involves the binding of antigens to antibodies to form immune complexes. 2. The second step is immune complex deposition, during which the complexes leave the plasma and are deposited into tissues. 3. Finally, the third step is the inflammatory reaction, during which complement is activated and macrophages and neutrophils are recruited to the affected tissues. Type III hypersensitivity reaction example (Arthus reaction): reaction known as serum sickness, can be triggered in sensitized individuals who possess IgG antibodies against the sensitizing antigen. E.g anti- TNF-a in rheumatoid arthritis Type IV hypersensitivity reactions or delayed-type hypersensitivity Mediated by antigen-specific effector T cells and take hours to days to develop  Mantoux tuberculin test Small amounts of tuberculin are injected intradermally People exposed to the bacterium, either by infection or immunization with BCG vaccine, a T-cell mediated inflammatory response with a visible swelling evolves over 24-72 hours. Erythema is recorded in mm. Celiac disease: has features of both allergic response and autoimmunity A chronic condition of the upper small intestine caused by immune response directed at gluten Pathology: loss of slender, finger-like villi formed by the intestinal epithelium, which normally absorb and digest food accompanied by inflammation of the intestinal wall with increased T cells, macrophages and plasma cells It has some features of autoimmunity – Autoantibodies against tissue transglutaminase are found in all patients with celiac disease; the presence of serum IgA Abs against this enzyme is used as a sensitive and specific test for the disease. Next…. Autoimmunity! 05/12/23