Immunity Session 6 PDF

Cell & Antibody-Mediated Immune Responses Dr Safeen O. Mahmood MB.Ch.B FKBMS Clinical Microbiology – infectious Diseases Learning Objectives By the end of this session, students should be able to: • • • • • • • • • • • • • Describe Cell-Mediated Immune Responses Recognize Cytotoxic T Cells and Ot...

Cell & Antibody-Mediated Immune Responses Dr Safeen O. Mahmood MB.Ch.B FKBMS Clinical Microbiology – infectious Diseases Learning Objectives By the end of this session, students should be able to: • • • • • • • • • • • • • Describe Cell-Mediated Immune Responses Recognize Cytotoxic T Cells and Other Effector Cells Identify Antigen-Presenting Cells Describe Helper T Cells (TH1 & TH2) and Memory T Cells Explain MHC Molecules (Class I & II) Describe Cytosolic & Endocytic Pathways Memorize TH1 and TH2 Cytokines Explain NK Cell-Mediated Cytotoxicity Explain ADCC Describe Antibody-Mediated Immune Responses Recognize B Cells & Plasma Cells Describe Antibodies Explain Follicular Dendritic Cells Immune System Module Immune response • Highly coordinated reaction of the cells of immune system and their products. • Two arms: o Humoral or Antibody-Mediated Immune response (AMI) o Cell-Mediated Immune response (CMI) Immune System Module Humoral Immune response • Provides protection to the host by secreting antibodies. • No role against intracellular antigens. Immune System Module Cell-Mediated Immune response (CMI) • Plays a crucial role in providing protection against intracellular microbes as well as tumor cells. • Mainly T cell mediated (especially cytotoxic T cells). • Other effector cells - NK cells, macrophages, granulocytes also play a role in mediating CMI. SEES Immune System Module CMI and AMI are interdependent • CMI and AMI cannot work individually. • Cytokines released from T cells stimulate B cells to produce antibodies. • Many effector cells of CMI (macrophages and NK cells) use antibodies as receptors to recognize the target cells for killing. • CMI also regulates the humoral immunity by releasing cytokines from activated T cells that stimulate the B cells to transform into antibody secreting plasma cells. See Immune System Module CMI and AMI are interdependent • Initial events - common to both CMI and AMI and they occur irrespective of the type of immune response that will follow. These events include: o Antigen presentation to helper T cells o Activation and differentiation of helper T cells into either 2 TH1 or TH2 subsets 00 Immune System Module CMI and AMI are interdependent • Helper T (TH) cells - central key that regulate the type of immune response. • Activated helper T cells differentiate in to either TH1 or TH2 subsets. o Induction of TH1 cells secrete cytokines that stimulate cell mediated response. o If TH2 cells are differentiated, they secrete certain cytokines thatein turn induce the B cells to produce antibodies. if TAZ stimulate lymphocytes_Am Immune System Module ANTIGEN PRESENTATION • T cells cannot recognize the native & free antigens. • T cells recognize antigen only after it is processed into smaller antigenic peptides containing specific epitopes which are subsequently combined with MHC molecules (class I or II) & presented on the host cell surface. Immune System Module Antigen- presenting cells (APCs) Professional APCs Nonprofessional APCs Dendritic cells Fibroblasts (skin) Macrophages Thymic epithelial cells B cells Pancreatic beta cells EE Vascular endothelial cells Glial cells (brain) Thyroid epithelial cells Immune System Module Antigen processing pathways • Cytosolic pathway: o Endogenous (intracellular) antigens (viral antigens and tumor antigens) are processed. o Presented along with MHC class I molecules to CD8 T cells. • Endocytic pathway: o Exogenous antigens (extracellular microbes and their products, e.g. toxins) are processed. o Complexed with MHC class II molecules and presented to TH cells. o Cells included: APCs such as macrophages, dendritic cells & B cells. E _e t Immune System Module Differences between cytosolic and endocytic pathways of antigen presentation Property Cytosolic pathway Endocytic pathway Antigen processed Endogenous Exogenous Antigen is complexed with MHC I molecules MHC II molecules Antigen is presented to TC cells TH cells Immune System Module HELPER T CELLS • Helper T cell (TH) activation and differentiation is the central event that regulates both the components of immune response; CMI and AMI. Immune System Module Activation of helper T cells • Activation of TH cells requires generation of three specific signals. o Antigen-specific signal: Binding of antigenic peptide present in the groove of MHC-II on APCs to TCR (T cell receptor) present on surface of TH cells. CD4 molecules of TH cells also interact with β2 domain of MHC-II. o Co stimulatory signal - Binding of CD28 molecule on TH cells to B7 molecules on APCs. o Cytokine signal - APCs (macrophages) secrete interleukin-1 (IL-1) which acts on TH cells. Immune System Module Activation of helper T cells produced's APC byTarelli Immune System Module • Essential for TH cell activation. transduction • Signal transduction Signal is initiated at CD4 molecule which interacts with CD3 complex which in turn transmit the signal leading to activation of TH cells. Immune System Module Differentiation of helper T cells • Activated TH cells secrete increased amount of IL-2 as well as IL-2 receptor (IL2R or CD25). • IL-2 binds to its receptors on the same TH cell and also on other TH cells and induces the naive TH cells to proliferate and differentiate. • TH cells get activated and become lymphoblast cells which subsequently differentiate into memory and effector TH cells. Immune System Module Effector TH cells • Derived either from the naive TH cells or pre-existing memory TH cells following antigenic stimulus. • Short lived (few days to weeks). • Further differentiate into either TH1 or TH2 subsets (crucial as they secrete distinct cytokines). 0 Immune System Module Role of cytokines secreted by TH1 & TH2 cells aheadnotreallyimp TH1 cytokines & their functions TH2 cytokines & their functions IL-2 IL-4 o IFN-γ 1. Promotes activation of TH and TC cells 2. Activates NK cells to become LAK* cells 1. Activates the resting macrophages into activated macrophage 2. Activates B cells to produce IgG 3. Promotes inflammation of delayed -type hypersensitivity (along with TNF-β) 4. Inhibits TH2 cell proliferation IL-5 IL-6 TNF-β Enhances phagocytic activity of macrophage IL-10 Immune System Module 1. Inhibits TH1 cell differentiation 2. Stimulates B cells to produce IgE and also IgG4 & IgG1 1. Enhances proliferation of eosinophils 2. Both IL-4 & IL-5 together provide protection against helminthic infections and also mediate allergic reaction Promotes B cell proliferation and antibody production Inhibits TH1 cell differentiation Role of cytokines secreted by TH1 & TH2 cells TH1 cytokines & their functions IL-2 1. Promotes activation of TH and TC cells 2. Activates NK cells to become LAK* cells IFN-γ 1. Activates the resting macrophages into activated macrophage 2. Activates B cells to produce IgG 3. Promotes inflammation of delayed -type hypersensitivity (along with TNF-β) 4. Inhibits TH2 cell proliferation TNF-β Enhances phagocytic activity of macrophage TH2 cytokines & their functions IL-4 1. Inhibits TH1 cell differentiation 2. Stimulates B cells to produce IgE and also IgG4 & IgG1 IL-5 1. Enhances proliferation of eosinophils 2. Both IL-4 & IL-5 together provide protection against helminthic infections and also mediate allergic reaction IL-6 Promotes B cell proliferation and antibody production IL-10 Inhibits TH1 cell differentiation Immune System Module Memory T cells • Derived from activated TH cell. • Longer life span (months to years). • They are in resting stage but following subsequent antigenic stimulus, they become activated and differentiated into effector TH cells. • Express CD45RO isoform of common leukocyte antigen CD45 as compared to naive T cells which express CD45RA. Immune System Module CELL-MEDIATED IMMUNE RESPONSE • Refers to destruction of cells carrying intracellular microbes and other abnormal cells such as tumor cells by various specific and non-specific cells of immune system, of which the most important is cytotoxic T (TC)cells. f Immune System Module • Provides immunity against microbes residing in intracellular Role of CMI milieuo For obligate intracellular organisms, CMI remains the only effective immune response. o For facultative intracellular organisms (bacteria like Listeria, Salmonella & Yersinia and fungi such as Histoplasma and Cryptococcus). Immune System Module Role of CMI • Immunity against tumor cells and other damaged & altered cells • Mediate delayed-type hypersensitivity (type IV hypersensitivity) • Plays key role in transplantation immunity and graft-versus- host (GVH) reaction. 5 1 Immune System Module Effector cells of CMI Effector cells of CMI Antigen specificity Cytotoxic T cells Specific NK cells Non-specific E Non-specific Cells performing ADCC* NK cells, macrophages, neutrophil & eosinophils Immune System Module Cytotoxic T lymphocytes • Principal effector cells of CMI, involved in the destruction of target cells such as virus infected host cells and tumor cells. • Naive TC cells (or CTL precursors) respond to viral or tumor peptide antigens which are processed by the target host cells (by cytosolic pathway) and presented along with MHC class I molecules. • Activated TC in turn secretes cytotoxic enzymes that lyse the target cells. Immune System Module Activation of CTL • Antigen-specific signal: o Induced by binding of TCR-CD3 complex of naive TC cells to MHC I -peptide complex of target cells. o CD8 of TC cells also interacts with α3 domain of MHC-I. • Co-stimulatory signal- CD28 of naive TC cells interacts with B7 f molecule on target cells. • Third signal – IL-2 (secreted by TH cell) acts on high-affinity IL-2 receptor on TC cells. Immune System Module Functions of CTL (Target cell lysis) • Activated TC cells produce two types of lethal enzymes: called perforins and granzymes. o Perforins produce pores in the target cell membrane; through which granzymes are released inside. o Granzymes are serine proteases; they induce cell death by apoptosis through caspase pathway. 8 Immune System Module Natural Killer Cells • Large granular lymphocytes that constitute 10-15% of It peripheral blood lymphocytes. • NK cells are cytotoxic but antigen non-specific. Is • Part of innate immunity - act as first line of defense and do not require prior contact with the antigen. • Act against virus infected cells & tumor cells till the TC cells are activated and take over the function. Immune System Module Comparison between NK cells and TC cells Property Surface markers MHC restriction NK cells CD16 & CD56 No TC cells CD3, CD8 MHC-I restricted Memory Immunity No Part of innate immunity Target cell Virus infected cells Tumor cells Perforins and granzymes (Constitutive) CMI Yes Part of acquired immunity Same as NK cells Mechanism of destruction Immune response Immune System Module Same as NK cells (Inducible) CMI Mechanism of NK cell mediated cytotoxicity • Receptor interaction: o Directly recognize certain ligands (e.g. glycoproteins) present on the surface of altered host cells like virus-infected cells or tumor cells. o Such ligands are also present on normal cells. o NK cells are capable of distinguishing normal host cells from the altered cells. o Mediated by two types of receptors present on NK cell surface (theory of opposing-signals model). Immune System Module Mechanism of NK cell-mediated cytotoxicity • Activation receptors (e.g. NKR-P1, CD16): o When these receptors are engaged with ligands present on the target cells; NK cells become activated. • Inhibitory receptors such as C-type lectin inhibitory receptors: o Recognize a part of MHC I molecule (HLA-E) which is present on the surface of all normal nucleated cells. Immune System Module Mechanism of NK cell mediated cytotoxicity In virus infected cells and tumor cells, the MHC-I expression is remarkably reduced. There won’t be any inhibitory signal. Binding of activation receptor to its ligand leads to activation of NK cells. Immune System Module Target cell destruction • Similar to that of TC cells i.e. via secreting perforins and granzymes. o Perforins forms pore on target cells, through which granzymes enter and lyse the target cells. o Only difference is that - enzymes are constitutively expressed in NK cell cytoplasm (i.e. they are cytotoxic all the time, even without exposure to the antigen). Immune System Module • NK cells respond to interleukin-12 (IL-12) produced by Alternative mechanism of NK cellwhich activity macrophages and secrete interferon-γ (IFN-γ), in turn activates the macrophages. • Activated macrophages phagocytose and kill the microbes. • NK cells also mediate their function via ADCC. Immune System Module Antibody-dependent cell-mediated cytotoxicity (ADCC ) • ADCC is exhibited by: o NK cells (secrete perforins, and granzymes) o Macrophages ( produce lytic enzymes and TNF) o Monocytes ( produce lytic enzymes and TNF ) o Neutrophils (releases lytic enzymes) o Eosinophils (lytic enzymes, perforins and immunity against helminths). Immune System Module Antibody-Mediated Immune Response (AMI) • AMI occurs through the following three sequential steps: o Activation of B cells following contact with the microbial antigen (B cells act as APCs). o Proliferation and differentiation of B cells into effector cells and memory cells. o Effector function- Secreted antibodies by plasma cells which in turn counter act with the microbes in many ways such as neutralization, opsonization, complement activation, etc. Immune System Module Activation of B cells • Antigens that activate B cells fall into two categories: o Most antigens are thymus dependent (TD): Activate B cells indirectly via activation of T cells. in TD antigens are processed by APCs presented to TH cells following which the activated TH cells cytokines that in turn activate the B cells. o Thymus independent (TI) antigens (e.g. bacterial capsule) are not processed by APC. They can directly activate B cells without the help of T cell induced cytokines. Immune System Module Antigen presentation of B cells to activated TH cells Recognition of microbial antigen (TD antigen) by B cell membrane immunoglobulin receptors (mIg) Receptor-mediated endocytosis of antigen. Antigen is processed into smaller antigenic peptides that are presented in complex with MHC-II to activated TH cells (by endocytic pathway). Leads to induction of two signals. Immune System Module Signal a induction • Signal-1 - Induced by the cross linking of mIg on B cell membrane with the microbial antigen. • Signal-2 - provided by binding of CD40 on B cell with CD40L (ligand) on activated TH cells. • Signal-3- Cytokine stimulus. Cytokines produced by the activated TH cells bind to specific cytokine receptor on B cells Immune System Module Signal transduction • Initiated by the B-cell receptor (BCR). The BCR comprises of two parts: o Antigen-binding membrane Ig o Ig-α/Ig-β heterodimer • Following antigen cross linkage to membrane Ig, the Ig-α/Ig-β heterodimer is activated and in turn transmits the signal, ultimately leading to activation of B cells. Immune System Module Proliferation and Differentiation of B Cells The naive B cells, released from bone marrow go and house in the B cell areas of peripheral lymphoid organs ( e.g. cortex of lymph node and marginal zone of spleen). There, the naive B cells are organized to form primary lymphoid follicles. • Following the antigenic exposure, the naive B cells are activated and then they proliferate. • Eventually, the primary lymphoid follicles transform into secondary lymphoid follicles. • Secondary lymphoid follicles bear a germinal center which in turn has two areas; dark zone and light zone. Events occurring in the secondary lymphoid follicles are as follows. Immune System Module Events in the Dark Zone of Genninal Center The activated B cells differemiate into larger dividing cells called centroblasts, which further transform into smaller non-dividing cells called centrocytes by expressing membrane lg. • Cemroblasts express the membrane lg by undergoing a type of mutation called somatic hypermutations. These are point mutations arising due to insertion or deletion in the variable region of lg gene. • This results in alteration of the membrane lg affinity by which it binds with the corresponding antigen. Thus, the resultant centrocytes would bear membrane Ig with altered affinity. Immune System Module Events in the Dark Zone of Genninal Center • Because somatic hypermutations occur randomly; they generate membrane lg with both high and low affinity. The centrocytes with low affinity membrane Ig undergo apoptosis and then are phagocytosed by special type of macrophages found in lymphoid follicles called tingible body macrophages. The centrocytes with high affinity membrane lg are allowed to survive, following which they migrate to the light zone. The process of enhancement of affinity of membrane Ig for antigen binding is called affinity maturation. Immune System Module Events in the Light Zone of Germinal Center • Binding of centrocytes to follicular dendritic cells: The cetrocytes with high affinity membrane Ig undergo maturation by binding to a special type of dendritic cell called follicular dendritic cell. Then the mature centrocytes undergo class switch over. Immune System Module Events in the Light Zone of Germinal Center • Class switch over: Early in the immune response, IgM is the predominant immunoglobulin secreted by the B cells. But as the maturation progresses, the same B cells undergo a phenomenon called class switch over to produce Ig of other classes. Class switch over occur in the light zone of lymphoid follicles, where the positively selected centrocytes interact with activated TH cells and receive a cytokine signal for class switching. Binding of cytokines produced by TH cells to cytokine receptors present on centrocytes surface induces class switch over. Different cytokines induce production of different classes of lg by switching mechanism. Immune System Module Events in the Light Zone of Germinal Center • Differentiation of centrocytes into plasma cells and memory cells: After undergoing class switch over, the selected centrocytes further undergo differentiation into effector cells (plasma cells) and memory cells in the light zone of germinal center. Plasma cells are large antibody-secreting cells; produce secretory lg enormously, but do not synthesize membrane lg. They do not have MHC-II molecules and do not undergo further class switch over. Memory cells bear high affinity membrane lg molecules of all classes as compared to naive B cell that bear only low affinity lgM or lgD membrane lg. They are long lived cells which respond to the secondary antigenic stimulus. Immune System Module Follicular dendritic cells • Differ from the other types of dendritic cells by: o Do not act as APCs and do not express MHC class II. Instead, they bear Fc receptors that recognize Ag-Ab complex. o Antigen is unable to move and is retained in the lymphoid follicle for prolonged periods so that the centrocytes can come and bind to the antigens present in Ag-Ab complex . o Allows the FDCs to interact with the centrocytes which results in the selection of the centrocytes with high affinity membrane Ig. Immune System Module Differentiation of B cells in secondary lymphoid follicles Immune System Module Cytokines secreted by TH cells and the respective Ig class/subclass they induce Cytokine(s) Ig class produced IFN-γ IgG2a or IgG3 IL-5 + TGF-β IgA or IgG2b IL-4 IgE or IgG1 or IgG4 IL-2,4,5 IgM IL-4,5,6 + IFN-γ IgG Immune System Module • Promotes opsonization o FcRs present on phagocyte surface recognize Effector of AMI antibody coated microbes, functions bind to them and that leads to enhanced phagocytosis. • Transcytosis o Poly Ig receptors are expressed on the inner (basolateral) surface of epithelial cells (facing the blood). o They bind to dimers of IgA and multimers of IgM antibodies and transfer them through the Opsonization of bacteria and phagocytosis cell to their apical (outer) surface and into the lumen of an organ (e.g., the intestine). Immune System Module Transcytosis of dimeric IgA Effector functions of AMI • Mediates mucosal immunity oTranscytosis of IgA to gut lumen provides mucosal immunity neutralizing the microbes at local mucosal sites. • Activates complement mediated inflammation and cytolysis o Antigen antibody complex initiates the complement activation via classical pathway. o Final complement factors (C5-C9), also called membrane attack complex has lethal activity by forming pores on the target cells. Complement-mediated cytolysis Immune System Module Effector functions of AMI • Promotes ADCC o ADCC is principally cell mediated; antibodies direct the cells to reach to the target cells. ADCC is important to provide a immunity againstHelminths, tumor cells and virus infected cells (NK cell-IgG mediated) Immune System Module Overview of Immune Response Immune System Module Learning Objectives: By the end of this session, students will be able to: 1. Summarize the role of reactive (atypical) lymphocytes in immunity against intracellular infections. 2. Infer the importance of T helper subtype 1 cells in the activation of macrophages and control of Mycobacterium tuberculosis infection. 3. Interpret the serology results of hepatitis B infection. 4. Relate the impact of uncontrolled diabetes on cytokine profile and wound healing. Case Study 1: A 22-year-old woman comes to the office due to 2 weeks of profound fatigue, which has prevented her from attending college classes. The fatigue was preceded by fevers and sore throat, but these have now improved. The patient is an exchange student and has no prior medical conditions. She does not use tobacco, alcohol, or illicit drugs. Vital signs are within normal limits. Oropharyngeal examination shows no abnormalities. There are several enlarged lymph nodes posterior to the sternocleidomastoid muscle bilaterally. Cardiopulmonary examination is unremarkable. The spleen is palpable 1 cm below the left costal margin. No skin rashes or other lymphadenopathy is present. Peripheral blood evaluation shows increased numbers of abnormal white blood cells as shown below. The observed cytoplasmic granules of these cells are most likely to contain which of the following substances? Explain and discuss your answer. A. Elastase fordigestion uses pancreaticenzyme B. lmmunoglobulins C. Major basic protein D. Perforin E. Ribosomes F. Viral capsid 8 eosinophils by released nonshat round Answer: minimal cytoplasm scalloped abundantcytoplasm D. Perforin This patient's peripheral blood smear reveals a reactive (atypical) lymphocyte. In contrast to normal lymphocytes, which are small, round, and have minimal cytoplasm, reactive lymphocytes are large, scalloped, and have abundant cytoplasm. Reactive lymphocytes are activated, pathogen-specific cytotoxic T cells and natural killer cells that form in response to certain intracellular infections (e.g., HIV, cytomegalovirus, toxoplasmosis); they are particularly linked to infectious mononucleosis, a primary Epstein-Barr virus characterized by fever, pharyngitis, adenopathy, splenomegaly, and severe fatigue (as is likely in this patient). Reactive lymphocytes are effector cells that contain cytotoxic granules composed of perforin (creates holes in the infected cell's membrane) and granzymes (enter the cytoplasm of infected cells and trigger cell death), which are released in response to foreign antigens on the surface (MHC class I receptors) of infected host cells. f Educational Objective: Reactive (atypical) lymphocytes are activated, pathogen-specific cytotoxic T cells or natural killer cells that form in response to certain intracellular infections. In contrast to normal lymphocytes, reactive lymphocytes are large, scalloped, and have abundant cytoplasm. Reactive lymphocytosis is a diagnostic feature of infectious mononucleosis. et Case Study 2: TB A 64-year-old man comes to the clinic due to several weeks of persistent cough, fever, and weight loss. He smokes a pack of cigarettes daily and drinks 10-12 beers on weekends. Chest x-ray reveals an infiltrate in the left e upper lobe. The patient is prescribed broad-spectrum antibiotic therapy for both aspiration and community-acquired pneumonia, but his symptoms worsen despite taking the medication as prescribed. Sputum Gram stain Eddie does not reveal any organisms. Lung biopsy findings are shown in the image below: Which of the following substances is most important for driving the development of this patient's observed microscopic lesion? Explain and discuss your answer. A. C3a B. Fibroblast growth factor regulatecell developmentanddifferentiation C. Granulocyte-macrophage colony-stimulating factor D. IL-4 E. Interferon-alpha F. Interferon-gamma antiviralcytokine inhibitreplicationofvirus Answer: F. Interferon-gamma This patient has cough, fever, weight loss, and an upper lobe lesion on chest x-ray, raising strong suspicion for active pulmonary tuberculosis.TB II Mycobacterium tuberculosis cannot be visualized on Gram stain due to the high lipid content (mycolic acid} of its cell wall. Most cases are diagnosed by acid-fast sputum testing and culture, but tissue microscopy typically shows granulomas characterized by epithelioid histiocytes and multinucleated Langhans giant cells. Granulomas often form after tissue macrophages encounter pathogens or substances that cannot be easily digested or removed. M. tuberculosis can evade intracellular killing by macrophages and reproduce within phagolysosomes. Infected macrophages present mycobacterial antigens to naive CD4 helper T cells in pulmonary lymph nodes and secrete IL-12, which induces activated T helper cells to differentiate into T helper subtype 1 (Th1) cells. Proliferating Th1 cells migrate to sites of infection, where they release interferon-gamma, which activates macrophages, improves intracellular killing of ingested mycobacteria, and recruits additional macrophages by increasing production of tumor necrosis factor-alpha. Activated macrophages can also limit the spread of mycobacteria by differentiating into epithelioid and giant cells that surround residual foci of mycobacteria, trapping them inside the necrotic, cheese-like area of a caseating granuloma. macro a Educational Objective: T helper subtype 1 cells release interferon-gamma, leading to the activation of macrophages, a process critical for control of Mycobacterium tuberculosis infection. Activated macrophages form mature phagolysosomes that destroy phagocytosed mycobacteria and can differentiate into epithelioid and Langhans giant cells to wall off extracellular mycobacteria within caseating granulomas. O Case Study 3: forHepatitis A 23-year-old man comes to the emergency department due to 7 days of fever and malaise. He has also had nausea and a poor appetite. The patient has no significant medical history but regularly uses injection drugs and has had multiple sexual partners. Temperature is 38 C. On physical examination, there is scleral icterus. A tender, smooth liver edge is palpable 4 cm below the right costal margin. Appropriate therapy is initiated. The following graph illustrates this patient's hepatitis 8 serologic markers over time. Which of the following best explains these observed findings? Explain and discuss your answer. A. Acute hepatitis B that progressed to chronic hepatitis with high infectivity B. Acute hepatitis B that progressed to chronic hepatitis with low infectivity C. Acute exacerbation of pre-existing chronic hepatitis B infection D. Immunity against hepatitis B acquired from vaccination during the hospitalization E. Recovery from acute hepatitis B infection with immunity against reinfection Answer: E. Recovery from acute hepatitis B infection with immunity against reinfection Serologic evidence of hepatitis B virus (HBV) exposure is present in 2 billion people worldwide. Perinatal transmission is most common in highincidence areas (e.g., sub-Saharan Africa). In low-prevalence countries such as the United States, Western Europe, and Canada, most cases arise due to unsafe sexual practices or injection drug use. Serological markers for HBV can be used to distinguish between acute infection, chronic infection, and a protective vaccination response. Acute HBV infection is marked by the proliferation of the virus in hepatocytes with the release of viral antigens (HBsAg , HBeAg ) and HBV DNA into the bloodstream and the generation of lgM against HB core antigen. Many patients with acute infection will have subclinical, anicteric disease, but approximately 30% develop several weeks or months of jaundice, fatigue, hepatomegaly, and elevated transaminases. Most adults with HBV clear the virus and generate protective immunity against future infection. This is reflected serologically by the following progression: 1. Anti-HBe antibodies develop 3-6 months after initial infection and are associated with the elimination of HBeAg. This correlates with reduced viral replication and infectivity. 2. HBsAg is eliminated around the time that HBeAg becomes undetectable. 3. Anti-HBsAg antibodies form several weeks /months later and provide protective immunity against future infection. plication ire c Educational Objective: The presence of anti-HBc and anti-HBs antibodies in the serum without detectable viral antigens indicates recovery from acute hepatitis B infection. In contrast, patients vaccinated against hepatitis B will have antiHBs antibodies without detectable levels of anti-HBc. Chronic hepatitis B is indicated by persistent levels of HBsAg and HBV DNA in the serum. Case Study 4: A 55-year-old man is evaluated due to a non-healing left forearm wound. The patient had an excisional biopsy of a suspicious skin lesion at the site of the wound several weeks ago. He has a history of uncontrolled type 2 diabetes mellitus and hypertension. Vital signs are within normal limits. Physical examination shows a 2.5 cm wound surrounded by erythema on the left forearm. Upregulation of which of the following would most likely improve fibroblast undneaing proliferation and reepithelization in this non-healing wound? Explain and discuss your answer. A. Bradykinin release from endothelial cells B. Cortisol release from the adrenal cortex C. Glycation cross-links in collagen fibers inflammatorycytokine anti D. Production of IL-10 by macrophages a E. Release of reactive oxygen species from neutrophils Glycation (non-enzymatic glycosylation) is the covalent attachment of a sugar to a protein, lipid or nucleic acid molecule. Answer: D. Production of IL-10 by macrophages This patient with a history of uncontrolled diabetes mellitus has a nonhealing wound with evidence of ongoing inflammation (e.g., erythema). Wound healing normally progress through the inflammatory, proliferative, and remodeling phases. In the days after the initial injury, neutrophils and other immune cells are recruited to the wound and produce an inflammatory response that helps prevent bacterial overgrowth in the nutrient-rich environment of a healing wound. However, this inflammation also impairs formation of granulation tissue that is needed for normal wound healing. As healing progresses, release of growth factors and antiinflammatory cytokines (e.g., IL-10) by macrophages and regulatory T cells suppresses the inflammatory response, facilitating fibroblast proliferation and re-epithelialization of the wound. In patients with diabetes mellitus, constitutively elevated blood glucose increases inflammation by stimulating the release of proinflammatory cytokines and reactive oxygen species from neutrophils. Elevated glucose also leads to a marked decrease in IL-10 production that contributes to the increased susceptibility for chronic, non-healing wounds and ulcers in patients with uncontrolled diabetes. Educational Objective: Is Elevated blood glucose induces the release of reactive oxygen species and proinflammatory cytokines from neutrophils while inhibiting the production of anti-inflammatory cytokines (e.g., IL-10) and growth factors needed for e fibroblast proliferation and re-epithelialization in a healing wound. As a result, patients with uncontrolled diabetes frequently have non-healing wounds with evidence of ongoing inflammation. 0