Session 20 - Type III and IV Hypersensitivity Reactions.pptx

Type III and IV Hypersensitivit y Reactions PBC 9700 Session 12 Randal K. Gregg, PhD Learning Objectives 1) Identify antigens, genetic predispositions, cytokines, antibody isotype and effector mechanisms of type III and IV hypersensitivity reactions. 2) Recognize diseases associated with type III an...

Type III and IV Hypersensitivit y Reactions PBC 9700 Session 12 Randal K. Gregg, PhD Learning Objectives 1) Identify antigens, genetic predispositions, cytokines, antibody isotype and effector mechanisms of type III and IV hypersensitivity reactions. 2) Recognize diseases associated with type III and IV hypersensitivity reactions. 3) Define immune complex and identify the mechanisms that remove them from circulation. 2 Type III and IV hypersensitivity 3 TYPE III HYPERSENSITIVITY 4 Type III hypersensitivity IMMUNE COMPLEX-MEDIATED HYPERSENSITIVITY Response to soluble Ag (self or microbial) IgG binds to the soluble Ag and forms immune complexes (IC) in the blood or tissues If not cleared – IC deposit in regions of the vasculature associated with high pressure o Glomeruli of the kidneys Nephritis o Blood vessel branches especially those with sharp turns Vasculitis o Joint tissue Arthritis Complement activation and FcR-mediated inflammatory responses develop and tissues are damaged (frustrated phagocytosis and MAC) IC are formed each time an Ig binds to a soluble Ag – normally the IC are removed by phagocytes in the spleen and liver 5 Clearance of IC in the spleen and liver 1 3 2 4 Deficiencies of factor I, C1, or C3 (or defects of CR1) can reduce IC clearance and the patient is more susceptible to type III reactions Factor I cleaves C3b to release the IC from RBC CR1 6 Pathophysiology of type III reactions IC form and deposit in the tissues (blood vessel shown to the right) IC binds C1 and activates the classical pathway of complement Cleaved complement factors C3a/C5a promote chemotaxis of neutrophils, monocytes and macrophages to the site of IC deposition (i.e. concentration gradient from the site of activation) Phagocyte FcR binds to the IC and CR to C3b to trigger activation of the cells Frustrated phagocytosis leads to release of mediators into the environment (prostaglandins, chemokines, lytic enzymes, ROS, NOS) In the blood vessels – neutrophils produce platelet activating factor (PAF) which induces platelet aggregation leading to the formation of microthrombi Prolonged phagocyte activation can lead to tissue necrosis 7 How does IC form in the presence of functional clearance mechanisms? 8 Chronicity and dose of the Ag can overwhelm the IC clearance mechanism Microbial Ag continually produced by active replication Self-Ag is continually present until the source organ is destroyed Some Ags are produced in large amounts at certain locations or during specific seasons of the year due to the organism’s optimal growth conditions 9 Rheumatoid arthritis (RA) Increases with age peaking 35-50y (3:1 f:m) HLA-DR4/DR1 present in 90% of patients o DR4 esp good at presenting citrullinated self-Ag (Arg residues are converted to citrullines by peptidyl arginine deiminases (PAD) o Smoking may induce PAD activity to generate self-Ag for RA T cells and PC accumulate in the synovium o T cells produce TNF- , IL-17, IL-1(Th1 and Th17); PC produce high levels of IgG and RF IC form and deposit in the articular cartilage and synovium Cytokines (+ PDG + LT) promote inflammation and tissue damage 80% patients are positive for Rheumatoid Factor (RF) o RF = multiple antibodies, mostly IgM (also IgG and IgA) directed against the Fc region of IgG; serves as a indicator of inflammatory and autoimmune activity o High titers of RF also in systemic lupus erythematosus, progressive systemic sclerosis, and dermatomyositis (and others) Chronic inflammation of the proximal interphalangeal and metacarpophalangeal joints can damage cartilage and bone (erosions) 10 Systemic lupus erythematosus (SLE) IgG develops against DNA, histones, ribosomes, snRNP (small nuclear ribonucleoprotein), and scRNP (small cytoplasmic RNP) IC form and deposit in many tissues triggering type III reactions leading to: o Glomerulonephritis (kidneys), arthritis (joints), and rash (face, butterfly rash) Broad Ig responses develop due to a process called epitope spreading (progressive cell and tissue destruction release more and more self-Ags for antibody to be generated) IC activate complement, recruit phagocytes, and lead to frustrated phagocytosis and MAC which destroys tissues over time; epitope spreading produces a chronic disease setting which often results in death of the patient due to failure of the kidneys or even brain HLA-DR3 confers the greatest susceptibility to SLE; but also HLA-DR2, -DR5 are susceptible Diagnosis of SLE if 4 of the following present Malar rash (flat or raised erythema over cheeks and bridge of nose; butterfly rash) Discoid rash (maculopapular rash in sunexposed areas) Photosensitivity Oral ulcers Arthritis (tenderness and swelling of >2 joints Pleuritis or pericarditis (documented by ECG) Renal disorder (proteinuria,  0.5g in 24 h) Neurological disorder (seizures without 11 Apoptosis is the key to SLE pathophysiology NORMAL APOPTOTIC BODY CLEARANCE Apoptotic bodies are opsonized by C1q, MBL, and pentraxins (C-reactive protein, CRP; serum amyloid protein, SAP; pentraxin 3, PTX3) Macrophages engulf and digest the apoptotic bodies Uptake of apoptotic bodies induces antiinflammatory cytokine secretion to prevent inflammation and suppress other immune responses by inducing T regulatory (Treg) activation 12 SLE Ags generated by impaired apoptosis IMPAIRED APOPTOTIC BODY CLEARANCE X Deficiencies in one or more of the opsonization factors, in particular, C1 Macrophages are unable to properly capture all of the apoptotic bodies Apoptotic bodies combine leading to rupture (necrosis) releasing compounds that bind TLR and Ags - UV may increase apoptosis Macrophages engaging this material are stimulated to produce IL-12 and TNF- DC are matured by TLR ligation and cytokine stimulation and also have taken up self-Ag from the necrotic material DC can activate self-reactive T cells (HLA association) B cells are activated and autoantibodies are made 13 B and T cell- and IC-mediated damage in SLE Self-reactive T cells are activated by mature DC (3 signals) o Defects of HLA presentation create a pool of self-reactive T cells in the lymph nodes and spleen Self-reactive B cells (paracortex) are activated by self-Ag and CD40 ligation and traffic to the follicle Activated B cells BCR- centroblasts (undergo somatic hypermutation) BCR+ centrocytes (affinity maturation with FDC) GC B cells engage TFH (CD40 ligation) isotype switching of GC B cells IL10/IL-21 promote PC differentiation Autoantibodies are produced, generally IgG and IgA Self-Ag is continually produced due to defective apoptotic body removal; autoantibodies bind the Ag to form IC IC accumulate due to defective IC clearance (deficiencies of C1, C2, and/or C4) IC can aggregate and deposit in tissues (blood vessels, kidneys, joints) trigger complement activation, phagocyte recruitment, frustrated phagocytosis, and MAC IC can also be captured by DC for another round of B and T cell activation (epitope spreading) Activated self-reactive T cells can traffick to sites of inflammation (IC deposition) and release cytokines to promote inflammatory responses and tissue damage 14 Other diseases associated with type III hypersensitivities 15 Type III hypersensitivity therapies RHEUMATOID ARTHRITIS (RA) Anti-TNF-(Infliximab or Remicade , Adalimumab or Humira) Anti-CD20 (Rituximab or Rituxanor Truxima) – removes B cells by NK cell ADCC Methotrexate – inhibits dihydrofolate reductase (no BH2 BH4 reduction rxn) and inhibits NF- B activation increasing T cell sensitivity to apoptosis SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) NSAID – control of inflammation, pain, swelling, and fever Corticosteroids – reduce Ig production Immunosuppressants (Azathioprine, Mycophenolate or Cellcept , Methotrexate or Trexall, Cyclosporine, and Leflunomide) Anti-CD20 Antimalarial drugs (Hydroxychloroquine or Plaquenil ) – modulates lysosomal pH and alters TLR signals Anti-IL-10 – block PC differentiation See notes below for more information CD40L CD40 CD80 CD28 CD86 16 TYPE IV HYPERSENSITIVITY 17 Type IV hypersensitivity DELAYED-TYPE HYPERSENSITIVITY (DTH) and T CELL-MEDIATED HYPERSENSITIVITY DTH so named because the symptoms become apparent 1-3 d after exposure to the Ag Response to soluble Ag (environmental, self or microbial) by T cells Classifications of type IV hypersensitivities: o Contact hypersensitivity (allergic contact dermatitis) o Granulomatous hypersensitivity o T cell-mediated hypersensitivity Different mechanisms of disease for each type – macrophages are one of the primary targets of the T cell activity 18 Delayed-type hypersensitivity CONTACT HYPERSENSITIVITY Also allergic contact dermatitis (ACD) Response that occurs in the skin at the site of contact with an allergen and occurs in two stages: Sensitization – first exposure “sensitizes” the cells to the allergen or generates a population of memory T cells that accumulate in the tissue Effector – upon re-encounter with the allergen memory T cells are activated to respond within 72 h Most common clinical manifestation is a rash 19 Contact hypersensitivity SENSITIZATION STAGE Contact allergens: o small molecules that easily enter the skin o can bind to TLR on tissue mast cells triggering activation and leading to some itching and scratching – enhances penetration o Some form conjugates with skin proteins – the contact allergen is the hapten and the skin protein is a carrier Haptenated proteins are captured and taken up by Langerhan cells (LC) and cutaneous dendritic cells (DC) o Effector memory Th1 cells are generated and traffick to the skin tissue where the allergen was first encountered and there reside o These DC process and present haptenated peptides (new Ags and NOT self) to T cells in the draining lymph node Generally it takes about 2 weeks for this process to occur No symptoms occur during this stage (although some mild itching could be induced by allergen entry as discussed) 20 Contact hypersensitivity EFFECTOR STAGE Re-exposure of the sensitized site to the same contact allergen – hapten again conjugates to skin protein LC/DC capture the haptenated protein and processes it for presentation of haptenated peptides to the local T cells The haptenated peptides are presented on both MHC class I and II molecules o Both CD4+ T cells (via MHC class II molecules) and CD8+ T cells (via MHC class I molecules) are involved in the generation of tissue inflammation Memory T cells are activated in both the epidermis and dermis CD8+ T cells (Tc1) produce lesions by inducing apoptosis of keratinocytes using release of perforin/granzyme and engagement of Fas ligand with Fas o Fas expression of keratinocytes is induced by TNF- , IL-1 , and IFN- 21 Contact hypersensitivity EFFECTORS Activated macrophages produce TNF- , IL-1 , and IL-6 to promote inflammation (endothelial adhesion molecules, vasodilation, increased vascular permeability); release lysosomal contents (i.e. hydrolytic enzymes) and reactive oxygen and nitrogen species (ROS, RNS) that degrade DNA and block enzymatic pathways of target cells (here the keratinocytes) = redness, inflammation, and blistering of skin Keratinocytes Express TLR that can bind the allergen leading to cytokine (IL-1 , IL-8, and TNF ) and chemokine production to enhance inflammation Mast cells Allergen can bind to TLR and trigger activation with histamine and cytokine release = itching Complement activation C5a activates mast cells with histamine and cytokine release = itching T cell-derived cytokines (TNF ) can also activate mast cells = itching As hapten levels drop – T regulatory (Treg) cells begin to suppress the inflammatory response and aid initiation of wound healing 22 Delayed-type hypersensitivity GRANULOMATOUS HYPERSENSITIVITY Represents a T cell response to persistent Ag (usually microbial) Microbes that establish chronic infections may be contained within a granuloma which is generated about 3 weeks after the initial infection A predominant CD4+ Th1 cell response is generated and the cells are recruited to the site of the chronic infection Macrophages in the tissues have phagocytosed the pathogen or are the target of the infectious agent (Mycobacterium tuberculosis is shown) Capture of the bacteria triggers the airway macrophages (alveolar macrophages) to penetrate into the underlying tissue Uptake of the bacteria engages TLR and induces macrophage release of IL-1 , IL-6, and TNF-to promote vasodilation, endothelial adhesion molecule expression, and increased permeability (i.e. inflammation) Th1 cells produce IFN-which activates macrophages in order to promote digestion of phagocytosed microbes 23 Delayed-type hypersensitivity GRANULOMATOUS HYPERSENSITIVITY After 2-3 weeks of activation the microbe is still not cleared Activated macrophages begin to differentiate into two populations: o o Epithelioid cells  Macrophages that resemble epithelial cells and are only found in areas of intense immune reactivity (i.e. high IFN-levels)  Some of the cells may be infected; epithelioid cells that fuse together form Giant cells  Secrete large amounts of fibroblast activating factor to stimulate fibroblasts to produce a fibrous capsule to quarantine the microbe Foamy cells  Macrophages that form lipid bodies due to a reduced efflux of low density lipoprotein (LDL)  Lipid bodies accumulate due to microbial stimulation of foamy cell TLR and the action of TNF-and MCP-1 (monocyte chemotactic factor-1)  MCP-1 can be produced by macrophages, endothelial cells, epithelial cells, neutrophils, and fibroblasts Maintain microbe in a non-replicating state – cells are not a sustainable host for the pathogen (little pathogen uptake, resistant to microbe-induced cell death, inhospitable for replication, produce TNF-and IFN- ) 24 Delayed-type hypersensitivity GRANULOMATOUS HYPERSENSITIVITY If the level of IFN-or TNF-is reduced (i.e. CD4+ T cell numbers) – quarantined microbe can begin to replicate by escaping the fibrous capsule o Epithelioid cells no longer maintain the fibrous cuff (powered by the cytokines) o Levels of lipid in foamy cells decreases – more susceptible to infection by the pathogen o Infected macrophages undergo lysis and the caseous necrotic center of the granuloma spills out into the tissue and airway releasing viable bacteria o Newly replicated bacteria gain access to the airway to trigger cough for transmission to other hosts (and symptoms in the patient) 25 Type IV hypersensitivity T CELL-MEDIATED HYPERSENSITIVITY Represents a T cell response to self-Ag (autoimmune diseases) Triggering event (infection, tissue damage, environmental, etc) leads to self-Ag release and DC maturation Local inflammation (macrophage and mast cell activation) recruits neutrophils and monocytes into the tissue DC present self-Ags to CD4+ and CD8+ T cells o Self-reactive T cells must escape tolerance mechanisms in the thymus in order to be able to persist in the lymph nodes and spleen (more on this in the tolerance and autoimmunity lectures) o Often these escape mechanisms involved defective HLA Ag presentation of specific self-Ags (i.e. derivation of organ-specific autoimmune diseases) Activated effector T cells migrate to the tissues, the source of the self-Ag Self-reactive CD4+ T cells produce cytokines to drive inflammation and activities of neutrophils, macrophages, and NK cells; Self-reactive CD8+ T cells recognize self-Ags and induce apoptosis of the tissue cells o Once outside of the thymus – self-reactive T cells must also escape other tolerance mechanisms to be activated by self-Ag B cells that have likewise escaped tolerance reside in the lymph node or splenic T cell zones; activated T cell engagement can rescue these self-reactive B cells and send them to the follicle for germinal center formation PC producing anti-self-Ag Ig migrate to the tissues and antibody-mediated destruction of tissues ensues 26 T cell-mediated autoimmunity is a type IV reaction 27 Type IV hypersensitivity (T cell-mediated autoimmune diseases) Disease T cell specificity Type I diabetes (insulindependent diabetes mellitus) Pancreatic islet cell Ags (insulin, glutamic acid decarboxylase) Rheumatoid arthritis Unknown self-Ag in joint synovium Multiple sclerosis Myelin basic protein Inflammatory bowel disease (IBD) Unknown Ag (gluten) Guillain-Barre syndrome P2 protein of peripheral nerve myelin Autoimmune myocarditis Myocardial proteins (post-viral myocarditis) 28