Basic Immunology 2 YR1 Lecture 1H PDF

Basic Immunology 2 Dr Timothy West Clinical Immunologist and Allergist, Campbelltown Hospital [email protected] 27 April 2022 1 Learning objectives 1. Distinguish between innate immunity and adaptive immunity 2. Identify the basic components of the immune system, including a basic outli...

Basic Immunology 2 Dr Timothy West Clinical Immunologist and Allergist, Campbelltown Hospital [email protected] 27 April 2022 1 Learning objectives 1. Distinguish between innate immunity and adaptive immunity 2. Identify the basic components of the immune system, including a basic outline of the principle cell types. 3. Identify the central and peripheral lymphoid organs and specify their organisation and functions 4. Outline the roles of the following cells; B lymphocytes, T lymphocytes, neutrophils, macrophages, dendritic cells, NK cells 2 Overview Recap the innate immune system. Overview of the adaptive immune response. Antigen presentation: MHC; T cells. Generation of lymphocyte diversity. B cells and antibodies. Actions of the adaptive immune system when it is activated. Memory, tolerance, immune defences against cancer. 3 Revision – key definitions Immunity: a state of resistance to disease, specifically infectious disease. Immune system: the body’s system for protecting us from foreign substances, principally infectious microbes, as well as cancer. Immune response: the coordinated response of the immune system in response to infectious microbes. Antigen: anything capable of eliciting an adaptive immune response. 4 Comparison of innate and adaptive immune systems Innate immune system Adaptive immune system Speed of response Fast: within minutes-hours. Slow: 2 – 7 days. Specificity Non-specific. Reacts to common shared patterns on surfaces of microbes. Specific. Reacts to antigens particular to an invading microbe. Diversity of epitopes recognised Thousands. > 10 million. Immunological memory No. Yes. Key anatomic components Skin, mucous membranes. Primary and secondary lymphoid organs. Key cells Phagocytes Antigen presenting cells Natural killer cells T lymphocytes B lymphocytes Key proteins Complement system Cytokines and chemokines Antibodies Cytokines and chemokines Found in Nearly all forms of life Jawed vertebrates. 5 Overview of the immune response If you get an infected cut on your finger… 1. The fact that bacteria have entered your tissues must be identified by cells resident within your finger. 2. Information about the bacteria, and a sense of danger, must be conveyed to the immune system at nearby lymph nodes. 3. An adaptive, targeted immune response must be generated. 4. A range of cells must enter the infected tissue, to kill the invasive microbes. 6 Overview of the immune response 1. 2. 3. 4. When a pathogen breaks an epithelial barrier, pathogen-associated molecular patterns (PAMPs) on its surface are detected by pattern recognition receptors (PRRs) on cells of the innate immune system, principally macrophages, causing cytokine release, complement activation and phagocytosis of antigens. The innate immune system triggers an acute inflammatory response to contain the infection. Dendritic cells, a key type of antigen presenting cell, present antigen to T cells of the of the adaptive immune system to trigger an adaptive immune response. T cells then coordinate an adaptive immune-response targeted at the invading pathogen: 1. 2. For extracellular pathogens (e.g. most bacteria), CD4+ helper T cells trigger B cells to produce antibodies. This is the humoral immune system. For intracellular pathogens (e.g. viruses) , CD8+ cytotoxic T cells directly kill virally infected cells. This is the cellular adaptive immune system. We covered (1) and (2) in the first lecture; we cover (3) and (4) today. 7 David Vetter had a normal innate immune system. However, he had no adaptive immune system. No adaptive immune system = not compatible with life. Severe combined immune deficiency (SCID). “Combined” = absence of both B cells (humoral immune system) and T cells (cellular immune system). This condition is universally fatal. Only solution = allogeneic bone marrow transplantation, i.e. for the patient’s defective immune system to be replaced with another person’s non-defective immune system. https://www.immunology.org/boy-in-the-bubble-1972 8 Key features of adaptive immune system Diversity – Many clones of lymphocytes, each clone responds to a distinct antigenic determinant. Specificity – All lymphocytes of a particular clone express receptors of one specificity and respond to that particular Ag only. Memory – After a pathogen has been eliminated, Memory T and B cells persist to allow more rapid clearance of that antigen following reinfection. 9 Innate Both innate and adaptive Pathogen breaches epithelial or mucosal barrier Detection of foreign pathogen Repertoire of lymphocytes able to specifically recognise any foreign pathogen 1 2 3 4 Time Immediate innate response to pathogen Adaptive Antigen presentation: triggering of adaptive immune response Generation of targeted immune response specific to the foreign pathogen 6 7 5 Innate and adaptive immune responses work together to clear pathogen Decline of immune response Immunological memory in case of reinfection 8 Extracellular pathogen recognition and elimination Many bacteria are extracellular: they can grow and reproduce freely in the body and do not need to (and cannot) enter inside of human cells. To detect these pathogens, the immune system only needs to look in the extracellular space; these bacteria cannot “hide” inside cells. – Professional APCs such as DCs and macrophages do this, by presentation of antigens captured from the extracellular space using MHC class II to CD4+ helper T cells. – Other cells of the body (e.g. epithelial, muscle cells etc) have no role in detecting extracellular pathogens. When eliminating these pathogens, only need to clear them from the extracellular space. – The humoral immune system is specially adapted to clearing larger, extracellular pathogens from the body. Once activated, CD4+ helper T cells stimulate B cells, to secrete antibodies to clear the pathogen. – The humoral immune system cannot target pathogens once they enter inside cells (e.g. viruses). 11 Intracellular pathogen recognition and elimination All viruses and some bacteria are intracellular: they infect the insides of cells. – Of course, for periods of time they must be outside cells too, e.g. in blood, respiratory secretions, etc. Thus, although professional APCs such as DCs may find them while they are outside cells, once they are inside human cells, they are hidden from DCs and from the humoral immune system. The cellular immune system is specially adapted to clearing intracellular pathogens from the body. Initial detection and activation of the adaptive immune system: As for extracellular pathogens, DCs still perform the early job of activating the adaptive immune system. – The DC acquires viral antigen if it is itself infected by the virus, or by phagocytosis / macropinocytosis of viral particles. Elimination of infection: Because viruses can potentially infect any nucleated cell, the cellular immune system must be able to find them inside any cell in the body. – All nucleated human cells are able to signal that they have been infected with an intracellular pathogen, via expression of viral antigens via MHC class I. – CD8+ cytotoxic T lymphocytes target and kill the infected human cells, thus (hopefully) killing the pathogens inside them. This process is not perfect: the immune system cannot clear many intracellular infections. – Viral e.g. hepatitis B, human papilloma virus, varicella zoster virus, HIV. – Intracellular bacterial infections e.g. tuberculosis (in many but not all hosts). 12 Broad divisions of adaptive immunity Immune system Innate immune system Adaptive immune system Humoral immunity T helper cells (CD4+) are involved in coordination of both humoral and cellular immune systems, although this lecture emphasises their role in the humoral immune system Involved in immunity against extracellular pathogens, particularly bacteria. Key components: B cells, plasma cells, antibodies, MHC class II. Cellular immunity Involved in immunity against intracellular pathogens, particularly viruses and certain bacteria. Key components: Cytotoxic T-cells 13 (CD8+), MHC class I. Types of lymphocytes Innate immune system Adaptive immune system Lymphocytes Lymphocytes which form part of innate immune system Cytotoxic T cells (CD8+ T cells) He Natural killer cells (NK cells]); innate lymphoid cells (ILCs) lps Cellular immunity: directly kills infected or damaged cells. Types of blood cells 1. Red cells 2. Platelets 3. White cells (aka leukocytes) a. Lymphocytes b. Neutrophils (innate) c. Monocytes / macrophages (innate) d. Eosinophils (innate) e. Basophils (innate) Out of scope for this lecture: Th17 cells T helper (CD4+ T cells) B cells (CD19+) Regulatory T cells (Treg cells) ps Th1 cell Th2 cell Assists in coordination of both cellular (Th1) and humoral (Th2) response. Th2 cells involved in allergy. l He Humoral immunity: produces antibodies; differentiates into plasma cells. 14 Involved in tolerance and regulation of immune response; suppresses other T cells. Terminology White cells = leukocytes. – Types of white cell: lymphocyte, neutrophil, monocyte/macrophage, eosinophil, basophil. Cells of the innate immune system are generally referred to by their individual name: neutrophil, dendritic cell, macrophage, eosinophil, etc. In the adaptive immune system, the word “lymphocyte” is confusingly often replaced with “cell”. – CD4+ T cell = helper T cell = CD4+ lymphocyte. There are two subtypes of helper T cell: Th1 cell, Th2 cell. Hence a “Th1 cell” is a “Th1 subtype of CD4+ lymphocyte”. – CD8+ T cell = cytotoxic T cell = cytotoxic T lymphocyte (CTL). – CD19+ lymphocyte = B cell. “CD” = cluster of differentiation = a protein on the surface of the cell used to identify it. 15 Innate Both innate and adaptive Pathogen breaches epithelial or mucosal barrier Detection of foreign pathogen Repertoire of lymphocytes able to specifically recognise any foreign pathogen 1 2 3 4 Time Immediate innate response to pathogen Adaptive Antigen presentation: triggering of adaptive immune response Generation of targeted immune response specific to the foreign pathogen 6 7 5 Innate and adaptive immune responses work together to clear pathogen Decline of immune response Immunological memory in case of reinfection 8 The two functions of antigen presentation Antigen presentation is involved in two key processes 1. Activation of the adaptive immune system. – This occurs in lymph nodes: dendritic cells of the innate immune system migrate to lymph nodes and presents antigen to CD4+ helper T cells. This process occurs for both extracellular and intracellular pathogens. – Activation of B cells also requires B cells to present antigen to helper T cells; for simplicity I have overlooked this in this lecture. 2. Clearance of intracellular pathogens (e.g. viruses). – This occurs in the infected tissue: any infected human cell presents antigen derived from intracellular pathogens that have infected the cell to CD8+ cytotoxic T cells. – This occurs later, once the adaptive immune system has been activated and CD8+ cytotoxic T cells have entered the infected tissue. 17 Lymphocytes circulate in blood, migrating through peripheral lymphoid tissues. Dendritic cells migrate from sites of infection to the draining lymph node. To activate the immune system, antigen presentation occurs in lymph nodes. Janeway’s Immunobiology, 9e, page 18 18 Antigen presentation First, inside antigen presenting cells (APCs; e.g. dendritic cells [DCs]), microbial proteins are broken down into short polypeptide chunks (antigens). – – For extracellular pathogens, the antigen is acquired when pathogens are phagocytosed, or from the extracellular fluid via micropinocytosis. For intracellular pathogens, the pathogen may have infected the DC; the DC may acquire antigen via micropinocytosis; or the DC may have phagocytosed an infected human cell. These antigens are then loaded into major histocompatibility complex (MHC) proteins expressed on the surface of the APC. The antigen, presented in MHC, interacts with the T-cell receptor on certain T cells to see if their receptor “matches” the antigen. Cytokines released by the DC provide a danger signal which notifies the adaptive immune system that the antigen being presented is potentially dangerous. IL-2 is the most important of these. If a lymphocyte finds its target antigen, presented properly in MHC, with the APC releasing appropriate danger signal cytokines, the lymphocyte is activated. After a foreign microbe is phagocytosed by an antigen presenting cell, it is killed and its proteins processed into short peptides (antigens) for presentation to the adaptive immune system. Janeway’s Immunobiology, 9e, page 13 19 Activation of lymphocytes When activated, lymphocytes proliferate and carry out effector functions to fight infection. Hold this thought! 20 The Major Histocompatibility Complex (MHC) MHC is a set of glycoprotein molecules which captures foreign antigen within the antigenpresenting cell and displays them on the cell surface. The function of MHC is to present antigens to T lymphocytes. The MHC molecule contains a cleft where the foreign antigen is held. The T cell receptor on T cells can only respond to antigen presented in the context of MHC (i.e. not to antigen floating around by itself). The T cell will be activated if it is exposed to its antigen presented in MHC, with appropriate costimulation and danger signals (certain cytokines). This is the immunological synapse. If antigen is presented in MHC but without costimulation and danger signals the T cell will either become anergic (inactive) or dies. This is one way in which self-tolerance is achieved. Janeway’s Immunobiology, 9e, page 13 T cell Antigen presenting cell 21 MHC I vs MHC II There are two types of MHC: MHC I and MHC II. MHC I is expressed on all nucleated tissues. It is used to present antigens from intracellular pathogens (e.g. viruses) to cytotoxic CD8+ lymphocytes. The cytotoxic CD8+ lymphocyte, if activated, will attempt to eliminate the virally infected cell. MHC II is expressed only by professional APCs. It is used to present antigens (primarily extracellular e.g. bacterial) to CD4+ helper T cells. The activated helper T cell will then stimulate B cells to produce immunoglobulin. MHC class I MHC class II Abbas & Lichtman, Cellular and Molecular Immunology, 9e, pages 129 and 130 22 T cell receptor The T cell receptor is a protein complex expressed on the surface of T cells that is responsible for recognising antigens presented in MHC. – The T-cell receptor on CD4+ helper T cells only interacts with MHC class II (i.e. only interacts with professional APCs). – The T-cell receptor on CD8+ cytotoxic T cells only interacts with MHC class I (i.e. can interact with any nucleated cell). For any given antigen, there may be only small number of lymphocytes which recognise that antigen. However, there are millions of distinct T cells in the body with distinct T cell receptors. T cell Antigen presenting cell – It is this variation (and similar variation in the B cell receptor) that allows the adaptive immune system to respond specifically to an individual invading pathogen, and to recognise potentially any pathogen. Janeway’s Immunobiology, 9e, page 13 23 Any nucleated human cell infected by an intracellular pathogen. Professional antigen-presenting cell (most importantly dendritic cell) Abbas’ Basic Immunology, 6th edition, figure 3.12. 24 Cellular vs humoral divisions of the adaptive immune system Humoral immunity. To fight off extracellular pathogens (e.g. many bacteria), antigen is presented by professional APCs (principally dendritic cells) via MHC class II to helper (CD4+) T cells. The T cells then trigger B cells to differentiate into plasma cells, which produce antibodies. Cellular immunity. To fight off intracellular pathogens (e.g. viruses, intracellular bacteria), antigen is presented via MHC class I to cytotoxic (CD8+) T cells. All nucleated human cells have this ability (as all can be potentially infected by viruses). This leads to activated CD8+ cells, which directly kill infected cells. – Recognition of intracellular pathogens also requires DCs to present to CD4+ cells; this phenomenon is known as crosspresentation. 25 Innate Both innate and adaptive Pathogen breaches epithelial or mucosal barrier Detection of foreign pathogen Repertoire of lymphocytes able to specifically recognise any foreign pathogen 1 2 3 4 Time Immediate innate response to pathogen Adaptive Antigen presentation: triggering of adaptive immune response Generation of targeted immune response specific to the foreign pathogen 6 7 5 Innate and adaptive immune responses work together to clear pathogen Decline of immune response Immunological memory in case of reinfection 8 Generation of lymphocyte repertoire Each naïve CD4+ (helper) or CD8+ (cytotoxic) T lymphocyte or CD19+ B cell bears receptors with just one single specificity. – We have so far only discussed the T cell receptor, found on CD4+ and CD8+ T cells. – We will discuss the B cell receptor in upcoming slides. There are lymphocytes of at least 10⁸ specificities in an individual human at any one time: the lymphocyte receptor repertoire. During development in the bone marrow (B cells), and in the thymus (T cells), millions of different genetic recombinations occur in the genes that encode for lymphocyte receptors, resulting in a lymphocyte clone being present to recognise almost every conceivable antigen. It is this diversity of receptors that gives the adaptive immune system the ability to recognise any pathogen it might encounter. Many lymphocytes that are potentially self-reacting undergo clonal deletion during development. Janeway’s Immunobiology, 9e, page 15 27 B cells (CD19+ lymphocytes) and antibodies B cells (CD19+ lymphocytes) are a key component of the humoral adaptive immune system. The B cell receptor on the surface of the B cells is the surface protein which allows it to recognise foreign antigens, analogous to the T cell receptor on T cells. – There are around 10⁸ different B cells in the body which can detect different antigens. – For any given antigen the immune system might encounter, there is both a B cell and a T cell that can recognise that antigen! The B cell receptor can be released into serum: this is antibody. – The T cell cannot do this with its receptor! Janeway’s Immunobiology, 9e, page 13 28 Antibodies Antibodies (B cell receptors) are Y-shaped proteins with two ends: 1 x constant region and the 2 x variable regions. The constant region is largely the same between all antibodies. – This is the end which attaches the antibody (B cell receptor) to B cells. – When released as antibodies, this end performs effector functions such as activating complement. The variable regions are the parts that can bind to antigen; this is where the B cell diversity is. There are different types of antibodies (IgM, IgG, IgE, IgA, IgD). – We will go through this in subsequent lectures. Janeway’s Immunobiology, 9e, page 13 29 Antibodies Antibodies can bind to their target antigen directly, wherever they encounter it. They do not require it to be presented to them in the context of MHC. As well as proteins from invading pathogens, antibodies can target carbohydrates, DNA, RNA, etc. – – – – Surface lipopolysaccharides on bacteria. Double stranded RNA from viruses. Toxins released by bacteria. Particles from ingested food e.g. peanut, leading to allergy. Because antibodies are Y-shaped, they can form antibody-antigen complexes in serum. (By comparison: T cells can only detect protein antigens that have been broken down into peptides by APCs and presented in the context of MHC) Janeway’s Immunobiology, 9e 30 Innate Both innate and adaptive Pathogen breaches epithelial or mucosal barrier Detection of foreign pathogen Repertoire of lymphocytes able to specifically recognise any foreign pathogen 1 2 3 4 Time Immediate innate response to pathogen Adaptive Antigen presentation: triggering of adaptive immune response Generation of targeted immune response specific to the foreign pathogen 6 7 5 Innate and adaptive immune responses work together to clear pathogen Decline of immune response Immunological memory in case of reinfection 8 The adaptive immune response Once an appropriate T cell is activated, it rapidly divides to produce thousands of clone of identical T cells. The lymphocyte activated will depend on the invading pathogen: either CD8+ cytotoxic lymphocyte for viruses (cellular adaptive immune system), or CD4+ helper lymphocyte for bacteria (humoral adaptive immune system). 32 Humoral adaptive immune response In response to extracellular pathogens such as bacteria, when activated, a CD4+ helper T cell: Releases cytokines to activate macrophages and promote inflammation. Signals to B cells to differentiate into plasma cells and release antibody. Abbas’ Basic Immunology, 6th edition, figure 1.9. 33 Humoral adaptive immune response B cells, after activation (by binding to antigen) and further stimulation from an activated helper T cell: Undergoes rapid proliferation. Refines its antibody to be more specifically targeted to the antigen that has invaded (affinity maturation; isotype switching). Differentiates into plasma cells which are highly specialised to produce large quantities of antibody. Abbas’ Basic Immunology, 6th edition, figure 1.9. 34 Actions of antibodies Antibodies have three main effects. 1. Bind to and neutralise toxins. 2. Coat the surface of invading microbes (opsonisation). This signals to macrophages that the microbe is foreign, so the macrophage phagocytoses it. 3. Trigger complement activation, leading to complement deposition on the surface of the microbe. This (1) promotes phagocytosis and (2) perforates the bacterium directly via the MAC. The latter two mechanisms show how the adaptive immune system can refine and target the adaptive immune system. Janeway’s Immunobiology, 9e, page 30 35 Cellular adaptive immune response In response to viruses, activated CD8+ cytotoxic T lymphocytes are attracted to and directly enter the infected tissue. – Interferon-ɣ and IL-12 are the key cytokines tgat promote CD8+ cell differentiation and proliferation. Cells infected by viruses express antigens from those viruses on their surface. Activated CD8+ cytotoxic T lymphocytes kill the virus-infected cells. – By releasing cytotoxic compounds including perforin, granzymes, and granulysin, which lead to apoptosis of targeted cell. CD4+ helper T lymphocytes assist macrophages to kill microbes they have ingested. Abbas’ Basic Immunology, 6th edition, figure 1.9. 36 Innate Both innate and adaptive Pathogen breaches epithelial or mucosal barrier Detection of foreign pathogen Repertoire of lymphocytes able to specifically recognise any foreign pathogen 1 2 3 4 Time Immediate innate response to pathogen Adaptive Antigen presentation: triggering of adaptive immune response Generation of targeted immune response specific to the foreign pathogen 6 7 5 Innate and adaptive immune responses work together to clear pathogen Decline of immune response Immunological memory in case of reinfection 8 Decline of the immune response Once the invading pathogen is cleared, the foreign antigen – the stimulus for the immune response – is removed. The immune response diminishes and ceases. Tissue healing can occur. 38 Innate Both innate and adaptive Pathogen breaches epithelial or mucosal barrier Detection of foreign pathogen Repertoire of lymphocytes able to specifically recognise any foreign pathogen 1 2 3 4 Time Immediate innate response to pathogen Adaptive Antigen presentation: triggering of adaptive immune response Generation of targeted immune response specific to the foreign pathogen 6 7 5 Innate and adaptive immune responses work together to clear pathogen Decline of immune response Immunological memory in case of reinfection 8 Immunological memory During the adaptive immune response, some T and B cells differentiate into long-lived memory T cells and memory B cells. These cells persist for years or decades, and facilitate much more rapid response to the same pathogen if it is encountered again. 40 Immunological memory Janeway’s Immunobiology, 9e, page 24 41 Innate Both innate and adaptive Pathogen breaches epithelial or mucosal barrier Detection of foreign pathogen 3 Repertoire of lymphocytes able to specifically recognise any foreign pathogen * 1 * But do not react to self antigen! 2 4 Time Immediate innate response to pathogen Adaptive Antigen presentation: triggering of adaptive immune response Generation of targeted immune response specific to the foreign pathogen 6 7 5 Innate and adaptive immune responses work together to clear pathogen Decline of immune response Immunological memory in case of reinfection 8 Self-tolerance It is really quite incredible that most humans’ immune systems can protect against many foreign pathogens, while not reacting to parts of themselves. 1. 2. Central tolerance: during lymphocyte development, selfreactive clones are killed or (for CD4+ T cells) develop into Treg cells. Peripheral tolerance: during antigen presentation, if costimulation and danger signals are absent, the T cell does not react (it may die, become anergic [non-responsive] or promote regulatory T cell activity). Abbas & Lichtman, Cellular and Molecular Immunology, 9e, page 212 43 Innate Both innate and adaptive Pathogen breaches epithelial or mucosal barrier Detection of foreign pathogen Time Immediate innate response to pathogen Repertoire of lymphocytes able to specifically recognise any foreign pathogen * 1 * But do not react to self antigen! 2 3 Adaptive 4 Antigen presentation: triggering of adaptive immune response The immune system is also involved in suppressing cancer 6 7 Generation of targeted immune response specific to the foreign pathogen 5 Innate and adaptive immune responses work together to clear pathogen Decline of immune response Immunological memory in case of reinfection 8 Immune defences against cancer As cancer cells mutate, they accumulate gene defects which lead to abnormal protein expression. These proteins, when expressed on MHC I, can cause the cancer cells to be targeted by the cellular adaptive immune system. … so cancer cells may stop expressing MHC I. NK cells, a lymphocyte subset that is part of the innate immune system, specifically target and destroy cells which do not express MHC I. 45 Innate Both innate and adaptive Pathogen breaches epithelial or mucosal barrier Detection of foreign pathogen Repertoire of lymphocytes able to specifically recognise any foreign pathogen 1 2 3 4 Time Immediate innate response to pathogen Adaptive Antigen presentation: triggering of adaptive immune response Generation of targeted immune response specific to the foreign pathogen 6 7 5 Innate and adaptive immune responses work together to clear pathogen Decline of immune response Immunological memory in case of reinfection 8 Summary: humoral immunity Abbas’ Basic Immunology, 6th edition, figures 3.12 and 3.17. 47 Summary: cellular immunity Abbas’ Basic Immunology, 6th edition, figures 3.12 and 3.17. 48 Question A 3 year old boy with recurrent severe bacterial infections would be more likely to have which of the following immunological abnormalities? A. A deficiency of NK cells. B. A defect in CD8 T cell function. C. A defect in production of MHC I molecules. D. Antibody deficiency. 49 Question A 3 year old boy with recurrent severe bacterial infections would be more likely to have which of the following immunological abnormalities? A. A deficiency of NK cells. B. A defect in CD8 T cell function. C. A defect in production of MHC I molecules. D. Antibody deficiency. 50 Question A 56 year old woman is being treated with azathioprine for her problem of Crohn’s Disease. Azathioprine acts against T cells. She presents with a localised skin rash. Which of the following infections may have caused the skin rash due to the effect of the azathioprine? A. B. C. D. Staphylococcal cellulitis. Shingles (Varicella-Zoster viral infection) Disseminated meningococcaemia. HIV primary infection. 51 Question A 56 year old woman is being treated with azathioprine for her problem of Crohn’s Disease. Azathioprine acts against T cells. She presents with a localised skin rash. Which of the following infections may have caused the skin rash due to the effect of the azathioprine? A. B. C. D. Staphylococcal cellulitis. Shingles (Varicella-Zoster viral infection) Disseminated meningococcaemia. HIV primary infection. 52 [email protected] 53