Immunology Y2S1.pdf

Immunology Problem 32 White cells and their functions Briefly describe the components of the immune system Innate immunity Adaptive immunity Both have 2 arms: o Humoral immunity o Cell-mediated immunity Briefly describe humoral immunity: function of compl...

Immunology Problem 32 White cells and their functions Briefly describe the components of the immune system Innate immunity Adaptive immunity Both have 2 arms: o Humoral immunity o Cell-mediated immunity Briefly describe humoral immunity: function of complement, antibodies in normal immunity Humoral immunity: mediated by molecules found in extracellular fluids o Complement proteins (innate) o Anti-microbial peptides (innate) o Antibodies (antidote) Function of complement: a protease cascade that complements the ability of antibodies and phagocytic cells to clear pathogens o Three activation pathways: § Classical pathway: activated by antibody binding to the pathogen § Lectin pathway: activated by binding of lectin to mannose molecules on pathogen surface § Alternative pathway: binding of complement to pathogen, in absence of antibody o Acts to: § Recruit and activate immune cells § Opsonisation (coating) of pathogens à promotes internalisation immune cells § Kills pathogens directly through lysis (formation of membrane attack complex) Antibodies in normal immunity o Produced by B cells (adaptive humoral response) o Development: § During B cell development, antibody gene rearrangement occurs in B cell progenitors à generates broad array of different antibodies § Each B cell produces antibodies that can recognise and bind the epitope on a single specific antigen with high specificity § Further rearrangement occurs following antigen recognition à increases binding affinity (affinity maturation) à fine-tunes antigen specificity 140  o Functions: § Agglutination: clump pathogen together, limiting spread § Opsonisation: binds pathogen and recognised by phagocytosis receptors on white cells à increases internalisation § Neutralisation: prevents binding of pathogen to host cells or interferes with toxin activity § Complement activation: classical pathway § Inflammation: activates immune cells in presence of pathogen § Antibody-dependent cell-medicated cytotoxicity (ADCC): initiates killing of pathogen by immune cells Briefly describe cellular immunity: types of white blood cells and their functions Cell-mediated immunity: involves the activation of immune cells, e.g. o Phagocytosis of bacteria by macrophages o Killing of infected/tumour cells by cytotoxic CD8+ T cells (CTL) Activated within hours/days Broad specificity, with limited memory All originate from a common progenitor cell in the bone marrow (haematopoietic stem cell à common myeloid progenitor) Cell type Description Function Macrophage Function shaped by local environmental cues à Phagocytosis, immune activation (mediator response tailored to pathogen type or production/release), antigen presentation, wound inflammation repair Dendritic Collect antigen in periphery à migrate to lymph Antigen presentation through MHC molecules, nodes à activate T cells cytokine production (activates T cells à promotes proliferation) Neutrophil Granulocyte à releases inflammatory molecules Phagocytosis, tissue damage, immune cell activation and recruitment Eosinophil Granulocyte à toxic mediators Multicellular pathogen clearance, allergies, asthma Basophil Granulocyte à anticoagulants and histamine Limit clotting, allergic responses Mast Granulocyte à release histamine Tissue resident, anaphylaxis and allergic responses Activated by IgE Natural Major cytotoxic cells of the innate immune Clearance of tumour or infected cells Killer (NK) system Innate Bridge innate and adaptive immune cells Rapid response to range of pathogens Lymphoid (develop from lymphoid pathway but do not TYPE 1: intracellular bacteria or virus à release IFNg (ILCs) express B/TCRs) à rapidly activated in response TYPE 2: multicellular parasites and allergy/asthma à to range of stimuli release IL-5 and IL-13 TYPE 3: extracellular bacteria à release IL-17 and IL- 22 141 Describe T and B cell development T lymphocyte development (cell-mediated adaptive immune system): o Lymphocyte progenitor enters the thymus from bone marrow o TCR rearrangement occurs in “double-negative” (DN) (CD4– CD8–) progenitors § TCR: dimer of an a and b chain § Gene locus contains cassettes à randomly combines to generate a wide range of TCRs à each can potentially recognise a different antigen § TCRa consists of V + J regions § TCRb consists of V + D + J regions § Constant region anchors receptor in cell membrane and provides intracellular signalling o Positive selection: T cells with a surface TCR that binds to MHC survive § Removes T cells that cannot interact with MHC o Negative selection: T cells activated by MHC and self-antigen are removed § “Central tolerance” – removes self-reactive T cells, that would cause autoimmune disease o Naïve T cells exit thymus and circulate in periphery T-cell type T Helper (Th) cells Cytotoxic T cells (CTLs) Memory T cells Suppressor/regulatory T cells (Tregs) Cell Express CD4 on cell Express CD8 on cell Persist long-term after Limit immune responses function surface surface initial activation (CD4 or à prevent Activated by antigen in Activated by antigen in CD8) autoimmunity and context of MHC-II context of MHC-I Rapidly proliferate upon inflammatory disease Activate antigen-specific Directly kill infected and re-exposure to antigen Release cytokines to B cells, CTLs, and tumour cells Provide long-term inhibit immune macrophages immune memory activation (e.g. IL-10) Subsets: Th1: intracellular pathogens and autoimmunity Th2: extracellular pathogens (e.g. parasites), allergy and asthma Th17: extracellular bacteria and autoimmunity 142  B lymphocyte development (humoral adaptive immune system): o Occurs in bone marrow, with unique B cell receptors (BCRs) on surface (plasma cells lack surface BCR/antibody) § Similar to TCR rearrangement § Consists of 2 heavy chains and 2 light chains § Heavy chain rearrangement occurs first: V + D + J loci § Light chain rearrangement occurs second: V + J loci § Specificity determined by combination of heavy and light chains o Positive selection: § Heavy chain rearrangement: Expressed on surface with germline encoded light chain = pre-BCR Surface expression required for survival § Light chain rearrangement: Functional surface BCR required for survival o Negative selection: self-reactive B cells are removed to prevent auto-immunity o Activation: § BCR binding to antigen (signal 1) à internalised for MHC-II presentation § Th cell support (signal 2) à TCR binds to MHC-II and antigen on B cell § Antigen-specific activation: B cell proliferation Differentiation and antibody class-switching Antibody release à alternative RNA processing removes transmembrane portion for secretion o Somatic hypermutation and affinity maturation § Prolonged antigen exposure (or repeat exposure) à somatic hypermutation and affinity maturation Occurs in germinal centres of secondary lymphoid organs § Somatic hypermutation: addition of mutation within the immunoglobulin gene variable region § Affinity maturation: B cells making antibody with higher affinity binding to antigen favoured o Antibody isotype switching § Antibody class (e.g. IgM, IgD, IgG) is determined by heavy chain constant region usage Occurs in B cell follicles in secondary lymphoid organs § Guided by cytokine stimulation = isotype/class-switching o B cell functions: § Antigen presentation Internalise pathogen using antigen-specific BCR Antigen is processed à presented to Th cells § Antibody production When activated by Th cells à release antibody à binds to a specific antigen Antibody/Immunoglobulin classes: o IgM: primary antibody in early response; fixes complement o IgD: co-expressed on cell surface with IgM prior to B cell activation; secreted form occurs after activation o IgG: highest concentration in blood; neutralises toxins and enhances phagocytosis o IgA: secreted into mucous, saliva, etc., as a dimer o IgE: involved in parasite response and allergy 143  § Immune memory: long-lived antibody-producing cells (plasma cells) survive to maintain long-term immunity Describe MHC antigens/HLA antigens/CD markers Major Histocompatibility Complex (MHC) antigens: o Display antigen on the cell surface o Activates adaptive immune cells o Allows recognition of infected/abnormal cells o MHC-I § Expressed by all cells, except RBCs § Display antigen from the cytoplasm (TAP/transporter associated with antigen processing transfers peptide on MHC-I) § Allow recognition of abnormal protein production (e.g. tumour) or virus infection § Recognised by CD8+ cytotoxic T cells o MHC-II § Expressed by APCs (dendritic cells, B cells, macrophages) § Display antigen from extracellular space § Activate responses against extracellular pathogens § Recognised by CD4+ Th cells Human Leukocyte Antigen (HLA): o Gene locus encodes the MHC genes o Each individual has multiple MHC-I and MHC-II genes, with a separate set from each parent o Broad allele diversity exists in the population o Allows for a wide range of antigens to be displayed and recognised Cluster of Differentiation (CD) markers: o Naming system for surface molecules on WBCs o Quantifies cell types and provides information on cell function/activation o Can be visualised using specific antibody reagents, which bind to each marker o e.g. § CD45: all immune cells § CD4: T-helper cells § CD8: cytotoxic T cells § CD14: monocytes § CD15: neutrophils Describe the development of adaptive immunity Failure of the innate immune response à adaptive immunity activation o Develops of days/weeks T lymphocytes: cellular immunity B lymphocytes: humoral immunity (antibody) Generates antigen-specific response Creates immunological memory after an initial response to a specific pathogen Dendritic cells are the primary APC: o Collect antigen in peripheral tissues à migrate to lymph nodes to activate T cells o Pathogens digested à antigens displayed on cell surface in MHC molecules o Antigen and MHC recognised by naïve T cells that are reactive to that specific antigen (signal 1) o Dendritic cells produce cytokines à activate antigen-specific T cells à promotes proliferation (signal 2) 144 Describe the basic principles of vaccination – antigen/antibody response (this lecture builds on week 11 learning points) Adaptive immunity leads to an enhanced response to subsequent encounters with that pathogen à less collateral tissue damage Long-term protection to repeat exposures later in life Concept underlying vaccination Using the examples of immune thrombocytic purpura and transfusion reactions, describe the consequences of immune intolerance of cell surface markers Thrombocytic purpura can be caused by the immune system mistakenly attacking and destroying platelets o If the cause of this immune reaction is unknown, the condition is called idiopathic thrombocytopenic purpura o In most children with ITP, the disorder follows a viral illness, such as the mumps or the flu o It may be that the infection triggers the immune system malfunction Transfusion reactions: if incompatible blood is given in a transfusion, the donor cells are treated as if they were foreign invaders, and the patient's immune system attacks them accordingly o Not only is the blood transfusion rendered useless, but a potentially massive activation of the immune system and clotting system can cause shock, kidney failure, circulatory collapse, and death Immunodeficiency and Immunosuppression, and their sequelae Describe the immune strategies for fighting different kinds of organisms: encapsulated and intracellular bacteria, viruses, prions, fungus Intracellular bacteria: o Enter cells to evade detection by immune cells e.g. myocobacterium tuberculosis (MTB) o Taken up by macrophage but do not induce phagosome fusion with lysosome and bacterial killing à bacteria divide/spread o Proteins from phagosome processed into MHC-II/peptide complexes on the infected cell surface o MTB-specific Th1 cells recognise bacterial antigen à produces IFNg à activates macrophage o Clearance: § Infected macrophage: activation to kill bacteria § Non-immune cell: induce apoptosis to kill cell and bacteria (MHC-I/CTL) Encapsulated bacteria: o Polysaccharide capsule resists uptake (e.g. Streptococcus pneumoniae) o Antibodies from adaptive B cells can bind to bacteria à activate complement and promote phagocytosis Virus: o Innate response: § Type 1 IFN release can protect target cells from initial virus infection § Viral infected cells reduce surface MHC-I expression à evade adaptive immunity NK cells kill cells expressing low levels of MHC-I 145  o Adaptive response: § B cells produce virus-specific antibodies à bind virus à prevent entry into target cells § CD8+ T cells recognise viral antigens presented in surface MHC-I à kill infected cells in virus-specific response Parasite: o Neutrophils and macrophages respond to initial tissue damage à fail to remove parasite o Pathogen-specific CD4+ Th2 cells activated by APCs à trigger immune activation: § Mast cells (by IL3/4/9) à release soluble factors to damage worm and recruit immune cells § Eosinophil (by IL-5) à release toxic mediators (e.g. eosinophil peroxidase, proteases) à damage pathogen § B cells (by IL-4) à produce pathogen-specific antibodies to bind surface and activate immune cells Describe the pathogenesis of immunodeficiency Cancer induced (leukaemia) o Uncontrolled proliferation of immune/blood cells may directly affect immune cell function or production o Disrupted bone marrow environment à impairs the normal development of immune cells o Cancer treatments interfere with cell proliferation § Chemotherapy and radiation therapy à suppresses cellular proliferation à limits tumour growth § Result in neutropenia (decreased neutrophil numbers) Impaired innate immune response Reduced phagocytosis Increased risk of infection Infection induced immunodeficiency o Pathogens (e.g. virus) can suppress immune responses to evade detection and/or clearance o Directly infect immune cells à interfere with function or cause loss of immune cells (e.g. HIV) o Secondary bacterial infection: § Primary viral infection à immune cell activation and lung pathology à impairs immune responses § Secondary bacterial infection: Reduced physical barrier Reduced mucociliary clearance Impaired immune cell function o HIV directly infects CD4+ T cells à progressive loss § Reduced immune cell activation (macrophage, B cells, NK cells, T cells) § Increased rates of opportunistic infection Drug induced immunodeficiency o Anti-inflammatory drugs e.g. corticosteroids § Reduce cytokine production § Reduce immune mediators § Reduce immune cell recruitment § Increase immune cell apoptosis 146  o Indications for corticosteroids: § Asthma § COPD § Ulcerative colitis § Rheumatoid arthritis § Multiple sclerosis o Impaired immune response à increased infections Transplant related immunodeficiency o Immunosuppressive drug treatment à prevents organ rejection o Otherwise CD8+ CTL and NK cells recognise donor tissue as non-self and induce apoptosis Genetically determined immunodeficiency o Primary immunodeficiency o Present early in life, often from birth o Severity and effect depends on: § Type of mutation § Gene affected o Selective IgA deficiency: § Most common primary genetic immunodeficiency § Specific genetic mutation unknown § B-cell defect: decreased IgA antibody but normal B and T cell numbers § Symptoms: 85-90% asymptomatic Recurrent infections in mucosal tissues § May generate autoantibodies against IgA à cause severe reactions to blood transfusion o Severe Combined Immunodeficiency (SCID) § Severe T and B-cell development defect § Multiple known genetic mutations adaptive immunity absent, no T cell or antibody responses § Symptoms: Severe, repeated infections in first 6-months Poor growth Chronic diarrhoea Death in early life (1-2 years), if untreated § Treatment: Management of infections Isolation to limit infection Enzyme replacement (adenosine deaminase) for ADA-SCID, where specific enzyme is deficient Antibody infusions Bone marrow transplantation, from matched donor lacking mutation Post-splenectomy o Spleen has important roles in: § Clearance of blood-borne bacteria § Removal of aged platelets/RBCs § Adaptive immune development (particularly memory B cells required for antibody responses) o Increased susceptibility to bacterial infections à sepsis 147  o Considerations: § Vaccination Limit bacterial infection Provided pre-surgery, where possible § Antibiotics Prophylactic daily – in children Immediately upon symptoms of infection § Limit travel to specific regions Describe the categories of immunodeficiency: acquired and innate – include the common causes of dysfunction of immune systems components such as B-cell, T-cell, neutrophils, complement Immunodeficiency: immune responses are compromised or absent Impaired innate immunity: rapid expansion of microorganisms, illness, and death, if untreated o Neutropenia due to chemotherapy o Anti-inflammatory treatment (e.g. corticosteroids) o Virus infection (e.g. influenza) à risk of secondary infection Impaired adaptive immunity: pathogen persistence and chronic infection o Primary immunodeficiency (e.g. SCID) – genetic defects in T/B cell development o Anti-inflammatory treatment (e.g. corticosteroids) o Virus infection (e.g. HIV) – loss of CD4+ T cells Primary immunodeficiency (~10%): intrinsic defects in immune molecule/cell typically caused by hereditary genetic, often present from birth or early life Secondary immunodeficiency (~90%): result secondary to an environmental factor (e.g. underlying disease, infection, treatment), appears later in life Immunosuppression: the reduction of the activation or efficiency of immune responses Describe the significance of unusual and recurrent infection (see Austin’s list of all the weird questions he was asked pre-transplant http://www.thisisaurl.com/page/3/) May indicate underlying immunodeficiency Early intervention is important Warning signs: o Ear infections o Sinus infections o Pneumonias o Abscesses o Thrush/fungal infections o Family history Problem 33 Drug allergies Briefly describe allergy (build on week 10, 19) Allergy: hypersensitive immune reaction in response to ‘harmless’ environmental factors (allergen à antigen) Allergen: innocuous antigen that causes the allergic reaction e.g. o Food allergens (wheat/dairy products) o Inhaled allergens (house dust-mite – HDM – pollens) o Medications (penicillin) Responses are determined by the route of exposure and the type of immune response activated 148  Sites of exposure: o Skin o Injection o Ingestion o Inhalation Allergic immune activation: o Allergen exposure to the epithelium à release of cytokines (IL-25/33, TSLP) o Activation of ILC2s o Activation of local APCs o T cell activation à Th2 cells generated in presence of IL-4 o B cell activation à IgE produced in presence of IL-4/Th2 o Mast cell activation by IgE à histamine release o Eosinophil activation by IL-5 In pre-sensitised individuals, allergen exposure causes: o Immediate, early response: mast cell activation and release of granular molecules o Late-phase response: § Activation of APC and Th2 cells § T cell proliferation § Activation of eosinophils Describe Type I-IV hypersensitivity reactions Allergen specific activation of mast cells stimulates release of a number of mediators à contribute to anaphylaxis o Histamine o Leukotrienes o Platelet-activating factor o Tryptase Symptoms of allergic hypersensitivity reactions differ based on: o Type of allergen o Underlying immune mechanism o Site of exposure 149  Reaction I (IgE- II (antibody-mediated) III (immune IV (cell-mediated) type mediated) complex) Immune IgE IgG and/or IgM IgG and/or IgM Th1 cells Th2 cells CTL reactant Antigen Soluble Cell- or Cell-surface Soluble antigen Soluble Soluble Cell- antigen matrix- receptor antigen antigen associated associated antigen antigen Effector Binding of Binding of Binding of Humoral IgG 1st exposure 1st exposure CD8+ T cell mechanism allergen to IgG to IgG to binds to blood- à CD4+ T à CD4+ T recognition IgE on cell allergen à antigen on borne allergen cells and cells and of allergen surface à complement cell-surface à insoluble MHC-II à MHC-II à on cell- cross-linking activation, receptors complex à differentiate differentiate surface à mast-cell FcR+ à alters complement and to Th1 cells to Th2 cells receptor à activation (monocyte) signalling à phagocyte à cytokine à IgE cytotoxicity and cells à antibody activation à release (IL12, production, degranulation opsonisation dependent tissue damage in IFNg, IL-2, eosinophil à histamine and cell- vasculature, and lymphotoxin) activation, release phagocytosis mediated locations of and immune mastocytosis OR cell lysis cytotoxicity complex cell (e.g. (NK cells) (ADCC) OR deposition (e.g. macrophage) antibody lung, skin, activation à interference kidneys, joints) cell damage with cell surface receptor à chronic stimulation OR impairment Timing 2-30 mins 5-8 hrs 2-8 hrs 24-72 hrs Example Allergic Some drug Chronic Serum sickness, Allergic Chronic Graft rhinitis, allergies urticaria arthus reaction contact asthma, rejection, allergic (e.g. (antibody dermatitis, chronic allergic asthma, penicillin), against tuberculin allergic contact atopic blood FC€RI alpha reaction rhinitis dermatitis eczema, transfusion chain) to poison systemic rejection ivy anaphylaxis, some drug allergies 150 Describe acute and catastrophic systemic immune responses to drugs Responses can differ in the same individual and between individuals Development of sensitisation may delay response on first exposure Rapid response occurs upon repeat exposure Symptoms: often relatively mild, but can be severe and life-threatening o Skin rash or hives o Itching o Wheezing or other breathing problems o Muscle and joint pains o Swelling/angiodema o Anaphylaxis – severe, potentially life-threatening Typically occurs within hours of taking the drug Common trigger include: o Penicillin and related antibiotics o Antibiotics containing sulphonamide (sulfa drugs) o Aspirin, ibuprofen, and other NSAIDs o Anticonvulsants o Chemotherapy drugs Mechanism (direct presentation/non-hapten) e.g. for sulfamethoxazole, lidocaine/lignocaine, mepivacaine, and celecoxib o Drug interacts with surface MHC molecules on APCs (presenting self- peptide molecules) à converts non-reactive self-peptide to reactive structure § Cross-presentation: drug can bind to MHC-I à moved to MHC-II to be recognised by CD4+ cells o T-cell screens MHC-peptide-drug complexes for TCR recognition o TCR binding à T-cell activation against drug Mechanism (hapten: binds to something à makes it immunogenic) o Hapten: drug irreversibly binds to carrier protein, which is displayed in MHC (e.g. penicillin) o Pro-hapten: inert drug molecules are processed into reactive metabolites à act as haptens (e.g. sulfamethoxazole) o Adaptive immune responses are then initiated through T-cell recognition of the drug-protein complex Adaptive response: responds as if that drug is a pathogen/allergen o Occurs through activation of all 4 types of hypersensitivty o Type of drug and immune envirnoment shapes the type of response activated o Symptoms and pathology are caused by the activated immune response Diagnosis: o Skin test – demonstrate specific allergic response to drug o Drug challenge – under carefully controlled conditions, if necessary Management and treatment: o Avoidance, where possible (use of alternate drug options) o Antihistamine treatment à suppresses allergic response o Bronchodilators, adrenaline, and oxygen à maintain blood oxygenation during respiratory distress o Desensitisation may be possible 151 Describe key cytokines associated with the allergic response (acute phase vs cytokine storm) Activation of T and B cells stimulates antibody production against drug (by B cells): o Cytokines guide antibody isotype switching o IgE produced when IL-4/Th2 cells present à Type I hypersensitivity (e.g. penicillin, cephalosporin) o IgG produced when IFNg/Th1 cells present à Type II/III hypersensitivity Activation of T cells, without B cell activation: type IV hypersensitivity o Sulfa antibiotics and b-lactams (e.g. penicilin derivatives, cephalosporin) Infection induced autoimmunity Describe the consequences of infection on allergic diseases Infection can worsen the symptoms of allergic diseases e.g. viruses exacerbate asthma symptoms o Baseline-inflammation due to asthma à increased inflammation driven by epithelium (e.g. IL-25) through viral interactions Describe the pathogenesis of atopic dermatitis and asthma Atopic dermatitis: o Often accompanies atopic respiratory allergy o Clinical course usually independent of allergen exposure o Very high IgE levels possible Asthma: o Triggered by allergen induced activation of submucosal mast cells à Th2 mediated chronic inflammation o Reaction initially driven by a response to a specific antigen o Subsequent chronic inflammatory process may be perpetuated even in the absence of allergen à could be triggered by factors other than the allergen 152 Describe the pathogenesis of microbial exacerbations of these illnesses Atopic dermatitis and microbial exacerbations: o Skin barrier defects (mostly genetic) à penetration by allergens and microbes o Chronic skin inflammation à trans-epidermal water loss o Vicious cycle: skin barrier defects + immune response + environmental triggers + inflammation o Defects in cell-mediated immunity à predominance of CD4 cells with Th2 cytokine profile o High levels of IgE o Common bacteria: Staphylococcus aureus, Streptococcus pyogenes o Viral infections are less common: HSV-1 most common (eczema herpeticum) Asthma and microbial exacerbations: o Virus-induced asthma exacerbation Describe viral induced autoimmunity, using the examples of: Hepatitis B and polyarteritis nodosa, Hepatitis C and cryoglobulinaemia and vasculitis, HIV and autoimmunity (haemolytic anaemia, ITP) Hepatitis B à polyarthritis nodosa o Hepatitis B: § Causative agent: virus Hepadnaviridae (DNA virus) § Disease progression Liver cirrhosis 2-5/100 5% of those with cirrhosis à develop hepatocellular carcinoma § Prevention: HBsAg vaccine (generates antibodies and CD4+ and CD8+ T-cells) § Therapy: IFN-a and anti-virals o PAN: § Necrotising vasculitis of medium-sized muscular arteries § Systemic necrotising inflammation of blood vessels § Presentation: myalgia, arthralgia, fever, weight loss, and multisystem disorders reflective of multiple organ system involvement § 70% of patients develop neuropathy due to inflammation of small arteries that provide to peripheral nerves (vasa nervorum) § Mostly observed in patients with hepatitis B due to circulating immune complexes (type III hypersensitivity) Ig and complement deposit (soluble antigens) in wall of involved vessels à vascular infiltration of neutrophils and mononuclear cells § Treatment: removal of Hep B Ags à antiviral therapy Hepatitis C à cryoglobulinaemic vasculitis o Hepatitis C: § Causative agent: RNA virus § Transmission: IV drug use, parenteral, sexual § Disease progression 60-80% develop chronic hepatitis 17-30% of those with cirrhosis à develop hepatocellular carcinoma § Complications: cryoglobulinaemic and non-cryoglobulinaemic vasculitis Cryoglobulins (CGs): Igs that precipitate when exposed to cold à redissolve upon warming § Therapy: IFN-a and anti-virals o Cryoglobulinaemic vasculitis § Molecular mimicry: HCV E2 protein antigenically similar to human Igs à stimulate anti-Ig Abs à stimulate complement cascade à form immune complex 153  § CG molecules formed are a mixture of polyclonal IgG and monoclonal Igs (usually IgM type) § CGs deposit in blood vessels à palpable purpura (haemorrhages) over low extremities, arthralgia, and neuropathy HIV à autoimmune haemolytic anaemia (AHA) OR immune thrombocytopenic purpura (ITP) o HIV: § Causative agent: HIV virus, envelope RNA virus (retrovirus) à enters cells by gp120 binding to CD4 (on T cells) and co-receptors à gp41 causes fusion between viral envelope and plasma membrane § Primary infection is asymptomatic/influenza like § Acute viremia à Ab production (seroconversion) § Period of clinical latency (2-15 years, i.e. no clinical signs of infection) Abs and CD8 cytotoxic responses directed against the HIV remain high during the asymptomatic phase Progressive loss of CD4 T-cells à increase in HIV number à decrease in Ab and CTL responses à opportunistic infections and malignancies (due to immunodeficiency) Oscillations due to mutations in the virus à perpetuates the infection Causes immune dysregulation – hypergammaglobulinaemia and autoimmune diseases o AHA: § Very rare in patients with HIV § Usually occurs in very advanced stages § Direct anti-globulin test can sometimes give false positive results o ITP: § 5-30% of patients with HIV § May be the first manifestation § Mechanism 1: peripheral platelet destruction with anti-GpIIIa (platelet integrin complex) Abs and activation of immune complexes § Mechanism 2: defect in platelet production due to infection of megakaryocytes § Treatment strategies: steroids, IV Igs, plasmapheresis, IFN-a therapy, splenectomy with retroviral therapy Describe bacterial induced autoimmunity, using the examples of: streptococcal illness and rheumatic fever, campylobacter and Guillian-Barre Streptococcal illness à rheumatic fever o Immune-mediated complication of GAS infection o Characterised by inflammation of the heart, joints, blood vessels, and skin o M protein: inhibits phagocytosis, inhibits complement deposition, binds host proteins, activates inflammation, adhesion, binds Igs o Molecular mimicry and breaking of tolerance: immune response against GAS à generates cross- recognition of human tissue proteins 154  Campylobacter infection à Guillian-Barre syndrome (GBS) o Acute inflammatory or post-infective demyelinating polyneuropathy o 70% of patients: history of respiratory infection or diarrhoea 1-4 weeks pre-onset o Some cases occur following surgery, or post-immunisation o Symptoms: weakness in legs spreading to upper body, pins and needles, difficulty with eye or facial movements, severe body ache, etc. o 25-50% with GBS have been exposed to Campylobacter jejuni o Molecular mimicry considered to be immunological mechanism: § Ab-mediated effector pathways (including complement activation) à glial or axonal membrane injury à conduction failure § Acute inflammatory demyelinating polyneuropathy: molecular mimicry between glycans in lipopolysaccharides (LPs) generating Abs à bind to GM1 and GD1a gangliosides à nerve conduction blockage Using the example of Group A Beta haemolytic strep infection, differentiate the principles of toxin-mediated illness vs direct infection vs post infectious illness Disease Toxin-mediated illness Direct infection Post-infection illness category Principles Scarlet fever Streptococcal pharyngitis Acute post-streptococcal and Associated with Strongly suggested by the glomerulonephritis symptoms uncomplicated GAS presence of fever; tonsillar Following infection with pharyngitis and tonsillitis exudate; tender, enlarged, ‘nephritogenic strains’ of Caused by the effect of anterior cervical lymph nodes; Streptococci streptococcal pyrogenic and absence of cough Involves immune complex exotoxins (SPEs) Incubation period of 2-4 days deposition (type III Diffuse erythematous rash, Characterised by sudden onset hypersensitivity reaction) blanching of sore throat, cervical Abrupt onset 1-4 weeks after Swollen, strawberry tongue lymphadenopathy, malaise, GAS throat or skin infection Toxic Shock Syndrome (STSS) fever, and headache Dark/smoky urine + Caused by SPEs à act as Younger patients may also periorbital oedema super antigens (stimulate develop nausea, vomiting, and Clinical recovery up to 10 primary T cells without being abdominal pain years processed by APC) Acute sinusitis manifests as 2/3 patients show complete 2-20% of T cells are persistent coryza, postnasal recovery stimulated by SAgs à drip, headache, and fever massive T cell stimulation à cytokine storm and multi- organ failure Faint erythematous rash on chest à multi-system shock- like state Adaptive immune response does not result following STSS 155 Problem 34 Autoimmunity of Connective tissue disorders Briefly describe central tolerance vs peripheral tolerance Central tolerance: o During lymphocyte development o In thymus (T cells) o In bone marrow (B cells) o T and B cell progenitors are produced with a broad array of antigen receptors (TCR or IgM) o Includes: § Negative selection: removes thymocytes that are capable of strongly binding with ‘self’-MHC peptides § Positive selection: selects for T cells capable of interacting with MHC molecules Peripheral tolerance: o After lymphocytes leave the primary organs (thymus and bone marrow) § Somatic hyper-mutation (selects for Abs that bind more tightly to a pathogen) à generates novel B-cell specificities within germinal centres à some may be able to bind to self- antigens à encounter of autoreactive B-cell with soluble antigen causes apoptosis o Mechanisms of peripheral tolerance: § Anergy: APC signalling via CTLA provides ‘off- signals’ to the reactive T cell T cell remains in circulation Functionally non-responsive to antigen (until a stronger signal is sent that can turn it back on) § Deletion: APC provides death signal à apoptosis of reactive T cell Occurs during persistent/repeated stimulation, as a mechanism to limit hyper- reactivity § Suppression: activation of Treg à limits activation of reactive T cells Define tolerance in regard to a specific antigen Immune tolerance: the failure to mount an immune response to an antigen Strategies are being developed in clinical trials to treat autoimmune disease by restoring tolerance: o Peptide-induced tolerance: delivery of soluble peptide à activates auto- reactive T-cells à apoptosis or anergy o Antigen-coupled cell-induced tolerance: causes T-cell tolerance and activates Th2 and Treg cells à suppresses autoimmune inflammation 156  o Altered peptide ligand (APL)-induced tolerance: activates Th2 and Treg cells with overlapping specificity à suppresses autoimmune inflammation Briefly describe how infection can be an autoimmune trigger via APC & lymphocyte activation, molecular mimicry, or release of sequestered antigens APC and lymphocyte activation (bystander activation) o Breakdown in tolerance mechanisms à self-antigen-specific T cell à binding to APC à signalling à binding to B cell à proliferation of B cell o Inflammatory mediators released during infection activate local dendritic cells o Provide danger signals to activate antigen presentation against the pathogen o Cause bystander activation of dendritic cells presenting self-antigen o Leads to activation of self-reactive T cells à downstream tissue damage Molecular mimicry o Some antigens generate adaptive immune responses that are ‘cross-reactive’ with self-antigen § Self-antigens share structural similarity with the antigen o An appropriate adaptive immune response develops against the pathogen à also reacts with self-antigen à autoimmune disease after infection is cleared Release of sequestered antigens o Some tissues are ‘immune privileged’ e.g. CNS, reproductive organs § Immune cell migration through privileged tissue is limited § Limited tolerance occurs to tissue specific antigens o Disruption of tissue barrier (e.g. following local infection) à release of sequestered antigen o Self-reactive lymphocytes (that underwent anergy instead of deletion à woken up) enter the tissue à activated by exposure to self-antigen Describe the types of autoimmune disease with examples and relevant autoantibodies; (review autoimmune to date: coeliac, thyroid, ITP) organ- specific (DM-1, Goodpasture’s, Graves, myasthenia) or systemic (RA, LE, SSc) with relevant clinical tests Local/organ-specific: targeting a single tissue/organ o e.g. type 1 diabetes mellitus targets insulin-producing islet cells in the pancreas o e.g. Graves’ targets thyroid Systemic: targeting multiple tissues/organ systems throughout the body o e.g. rheumatoid arthritis § Blood tests: ESR and CRP: elevated à indicative of systemic inflammation Rheumatoid factor: auto-antibody that binds to Fc region of IgG (>20 IU/mL) Anti-CCP antibody: ~90% specificity for RA § Imaging: x-ray, ultrasound, MRI, for changes in joint structure 157  o e.g. systemic lupus erythematosus (SLE) targets histones or DNA, found in all cell types § Antibody testing: ANA, anti-dsDNA Describe the pathogenesis of autoimmunity in regard to connective tissue disorders Pathology is dependent on the type and location of connective tissue affected Pathogenesis of RA: o Antigen: within joint/bone tissue (specific antigen is unknown) o Immune activation: § Localised damage within joint synovium à attracts immune cells § Auto-reactive CD4+ T-cell activation à activate tissue macrophages § Inflammatory cytokine release à ongoing local tissue damage TNF-a: stimulates inflammation Matrix metalloproteinases (MMPs): degrade ECM RANK ligand: activates osteoclasts that dissolve bone Pathogenesis of SLE: o Antigen: adaptive immune response develops against: § Histone H1 – key component of DNA chromatin packaging § DNA o Immune mechanism: § Activation of histone H1-specific helper T-cells § Activation of H1 or DNA-specific B-cell response § Production of anti-H1/DNA antibody o Immune response can target any cell à broad range of symptoms and pathology Describe the concept of genetic disposition with environmental trigger (UV light in SLE, hygiene hypothesis) Triggers: altered cytokine activation o Altered cytokine levels may contribute to development of autoimmune disease o Increased inflammatory cytokine level à increased adaptive immune activation o Decreased anti-inflammatory cytokine level à reduced tolerance mechanisms Environmental triggers: UV light and SLE o Skin lesions affect up to 90% of patients with SLE o UV exposure à induces epithelial cell death à release of self-DNA à binding by anti-H1/DNA Abs à immune complex formation and immune activation à worsening of symptoms o UV light may also be a trigger for SLE onset (evidence is less clear) o Simultaneous infect may also contribute, in genetically susceptible individuals Environmental triggers: hygiene hypothesis o Lack of early childhood exposure to infectious agents and symbiotic microorganisms (e.g. gut microbes or probiotics) à increases susceptibility to allergic and autoimmune diseases o Suppresses the natural development of the immune system o Early life exposures interact with genetic factors to alter the likelihood of developing autoimmune disease later in life 158 Problem 42 Autoimmune processes in the Nervous System Describe the pathogenesis of autoimmune diseases in the CNS, including: Pathogenesis of Multiple Sclerosis (MS) o Hallmarks: CNS inflammation and neurodegeneration o Trigger aetiology unknown: § Increased risk from specific HLA regions on chromosome 6 associated § Strong epidemiological link with EBV (molecular mimicry?) o T-cell-mediated neurodegenerative disease against CNS myelin antigens, e.g. myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte protein (MOG) o Sclerotic lesions or plaques develop in the white matter of CNS o Destruction of myelin sheath surrounding nerve cell axons, with inflammatory infiltrates of macrophages and lymphocytes surrounding blood vessels o Immunopathogenesis: presence of potentially autoreactive T-cell pool, combined with unknown systemic trigger à initiates release § Autoreactive T-cells specific to myelin antigens migrate into CNS tissue § T-cells encounter autoantigen peptides presented by MHC-II on infiltrating macrophages and microglial cells à become activated (in CNS or periphery) § Local inflammatory response increases vascular permeability and promotes infiltration of autoreactive Th17 and Th1 effector cells § Inflammatory cytokines (e.g. IL17, IFNg, and GM-CSF) increase inflammation and local recruitment of lymphoid and myeloid cells into CNS § Autoreactive B-cells produce autoreactive Ab with T-cell help à exacerbates inflammation o Characterised by acute attacks and reduction of disease (relapsing-remitting nature) § Course can continue for decades, followed by secondary progressive MS, where patients undergo steady neurological decline à become unresponsive to treatment § Ultimately exhausts the capacity of the CNS to regenerate Pathogenesis of Autoimmune Encephalopathies o Diverse group of neuro-psychiatric disorders presenting acutely or sub-acutely with alteration of consciousness, cognitive decline, seizure, and abnormal movements o Associated with systemic autoimmune disorders, CNS autoimmune disorders and paraneoplastic syndromes o Likely to be mediated by Abs to CNS proteins à directed against membrane receptors and ion channel-associated proteins that are expressed on the surface of neurons in the CNS, e.g. § N-methyl D-aspartate receptors and leucine-rich, glioma inactivated protein and contactin- associated protein like, that are associated with voltage-gated potassium channels o Not invariably cancer-related à different from the classical paraneoplastic neurological diseases that are associated with, but not caused by, Abs to intracellular proteins Pathogenesis of Autoimmune Cerebellar Disease (anti-Hu) o Anti-Hu: a type of paraneoplastic neurological disorder (PND) § PND: neurological manifestations associated with cancer § Do not originate from tumour itself à caused by metabolic, toxic, or infectious complications of malignancy and/or treatment 159  § Highly diverse in terms of tissue damage and clinical signs § Can develop due to naturally occurring anti-tumour immune responses o Anti-Hu syndrome associated with lung cancer in 85% of cases (mostly SCLC) o Heterogenous disorder with highly diverse clinical and pathological manifestations in terms of lesion sites, inflammatory infiltrates and neuronal damage o Symptoms can include psychiatric (e.g. depression, anxiety, hallucinations) and neurological (e.g. memory loss, weakness, seizures, coordination problems) o Regions preferentially targeted are: hippocampus, lower brain stem, spinal cord, and DRG o Immunopathogenesis: vigorous adaptive immune response developed against (newly) ectopically expressed antigen HuD by SCLC cells à tissue-resident DCs capture antigens from malignant cells § DCs migrate to lymph nodes à presented to CD4+ and CD8+ cells § Activated tumour-specific T-cells occur within neoplastic lesions à cancer cells expressing MHC-I and HuD-derived peptides à recognised and killed by HuD-specific CD8+ cells § In parallel, HuD-specific T-cells circulate and acquire the capacity to cross the BBB § In CNS, neurons express MHC-I and present peptides derived from the highly homologous HuD, HuB, HuC proteins § Neurons are targeted by HuD-specific CD8+ cells à neuronal tissue damage à paraneoplastic neurological manifestations Pathogenesis of Anti-N-methyl-d-aspartic acid receptor (NMDAR) psychosis o Associated with Abs against NR1 or NR2 subunits of the NMDA receptor § Typically associated with presence of teratomas o NMDAR: a glutamate receptor and ion channel protein in nerve cells à controls synaptic plasticity and memory function o Clinical features: auditory and visual hallucinations, delusions, behavioural change, impaired consciousness, motor disturbance, seizures, and autonomic dysfunction o Neuropsychiatric presentation of anti-NMDAR encephalitis provides important support for the NMDAR hypofunction hypothesis for psychosis o Acute psychosis in anti-NMDAR encephalitis is associated with serum and CSF IgG Ab against the NR1a subunit of NMDAR § Abs against different antigens have been described in cases of limbic encephalitis and SLE o First-line treatment: immunotherapy, typically corticosteroids, IV Igs or plasma exchange, in addition to the removal of any identified teratomas Explain in detail the pathogenesis of autoimmune diseases in the Peripheral nervous system, including: Pathogenesis of Guillain-Barre Syndrome (GBS) o Acute inflammatory or post-infective demyelinating polyneuropathy o History of respiratory infection or diarrhoea 1-4 weeks pre-onset in 70% of affected o Some cases occur following surgery, or post-immunisation o Molecular mimicry is considered to be the immunological mechanism when infection causes GBS o Ab-mediated effector pathways damaging the myelin sheath, including complement activation o Cause glial or axonal membrane injury with consequent conduction failure o Acute inflammatory demyelinating polyneuropathy: molecular mimicry between glycans in LPS, generating Abs that bind to GM1 and GD1a gangliosides à nerve conduction blockade o Axon or end-plate terminal damage: less common variant of GBS § Mediated by anti-ganglioside IgG Abs § Symptoms depend on type of ganglioside targeted § Nerve damage is caused by classical complement activation 160  Pathogenesis of Myasthenia Gravis o Characterised by progressive inability to sustain a maintained or repeated contraction of striated muscles o ACh receptors in the post-junctional membrane of the NMJs are blocked or internalised by a complement-mediated autoimmune reaction § ACh receptors bound by anti-ACh receptor Abs o Usually presents with intermitted ptosis, diplopia, weakness of chewing, swallowing, speaking, and limb movement Pathogenesis of Lambert-Eaton Myasthenic Syndrome (LEMS) o Uncommon disorder of NMJ transmission o Primary clinical manifestation of muscle weakness mostly of the lower extremities o Association with SCLC o Reduced ACh released from presynaptic nerve, despite normal ACh vesicle number, normal ACh presynaptic concentration, and normal postsynaptic ACh receptors o Abs to pre-junctional voltage-gated calcium channels interfere with ACh release at nerve terminals and conduction of the electrical signals from the neuron to muscle cells o Distinguished from MG by the presence of: muscle stiffness, autonomic changes, absence of deep tendon reflexes with increase in muscle strength with repetitive muscle contraction Neurotropic infections Describe neurological infections and immune responses Neurotropic pathogens (bacteria, viruses, and parasites) gain access to the CNS parenchyma or CSF compartments (includes SA space and the ventricular system) Macrophages and microglia detect foreign pathogen entering CNS à become activated Chemokines and anti-viral cytokines (e.g. interferons) act on the local environment o Increased expression of cytokines and chemokines modulates brain function via effects on dopaminergic pathways, and glutaminergic pathways Chemokines attract T-cells and myelomonocytic cells from the periphery Upregulation of MHC molecules and Ag presentation on infected microglia, macrophages, stromal cells, and astrocytes Enhancement of T-cell mediated immune response Clinical features depend on the location of the disease process Rates of infection vary according to geographical regions Symptoms severity varies according to the pathogen Immune responses also vary according to the infectious agent Describe neurological tolerance, immune privilege, molecular mimicry of pathogens CNS was considered to be an immune-privileged area due to: o Existence of BBB o Absence of lymphatic drainage 161  o Low expression of MHC-II o Low levels of DC and potent APC (microglia play a role in Ag presentation) o Secretion of immunosuppressive TGF-b During infections there is a breakdown in tolerance à peripheral T-cells gain access to the CNS through BBB Evidence shows: CNS is an active surveillance site with bi-directional communication between the CNS and the immune system Molecular mimicry of pathogens in CNS: o Links between viral infection, autoimmunity, and neurological disease in humans (e.g. MS) o Genetic predisposition and molecular mimicry à migration of autoreactive T-cells through BBB into CNS o Microglial cells present myelin peptides to activate T-cells o CD4+ Th1 cells activate local macrophages and astrocytes to reduces myelin synthesis or trigger neuron apoptosis o CD4+ Th2 cells induce B-cell activation and formation of myelin reactive Abs à auto-Abs trigger demyelination Describe the genetic aspects of susceptibility to neurological infections In TB, as with other infectious diseases, both the genetic makeup of the microbe and the genetic make-up of the human work together to create pathways and to regulate the success or failure of the microbe e.g. mutations in IFN-g receptor 1 àinability to upregulate TFN and IL-12 and the inability to upregulate IFN-g itself in response to IFN-g stimulation Describe sequestration and the blood-brain barrier Cerebral malaria: a serious neurological condition where sequestration is considered to play a major role in pathogenesis o Endothelial damage associated with the sequestration of Plasmodium falciparum schizonts within the microvasculature of the brain Adherence of infected RBC by Plasmodium falciparum Erythrocyte Membrane Protein (PfEMP1) DC8 and DC13 variants to endothelial receptors (EPCR and ICAM-1) à sequestration and reduction in microvascular flow Combination of parasite variant surface antigen PfEMP1, its receptors, coagulation, and host endothelial cell activation (or inflammation) à pathogenesis of cerebral malaria is a multifactorial disease 162