Hypersensitivity reactions multiple mechanisms Notes

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Hypersensitivity pneumonitis

Transplant rejection

Chapter 2 Acyanotic Defects NOTES HYPERSENSITIVITY REACTIONS: MULTIPLE MECHANISMS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Hypersensitivity (intolerance): undesirable reactions produced by immune system (e.g. allergies, autoimmunity) ▪ Range from minor (e.g. swelling, itching) to tissue-damaging, fatal ▪ Multiple mechanisms indicates the presence of two or more of the four types of hypersensitivity reaction ▫ Type I: allergy, acute hypersensitivity ▫ Type II: antibody-dependent cytotoxicity ▫ Type III: immune complex disease ▫ Type IV: delayed type hypersensitivity/ cell-mediated immune memory response ▫ Tissue specific antibody response: autoimmune disease/organ rejection Common Hypersensitivity reactions with multiple mechanisms ▪ Hypersensitivity pneumonitis ▪ Transplant rejection ▪ Latex allergy (I+IV) ▪ Sjögren syndrome ▪ Autoimmune hepatitis Autoimmune polyendocrine syndrome (APS1, APS2) ▪ Autoimmune adrenalitis ▪ Systemic autoimmune disease SIGNS & SYMPTOMS ▪ Non-specific flu-like symptoms (e.g. fever, chills, malaise, cough, joint pains) ▪ Multiple mechanisms varies by location; see individual disorders DIAGNOSIS LAB RESULTS ▪ Acute (Type I) hypersensitivity ▫ Spirometry/pulmonary function, skin tests (exposure to specific allergens provokes skin reaction), radioallergosorbent tests (quantify allergen specific IgE levels) ▪ Type II–IV hypersensitivity ▫ Identify organ/cell component specific antibodies Biopsy (Type II–IV hypersensitivity) ▪ Immune cell infiltration of organ ▪ Compromise of normal organ anatomy TREATMENT MEDICATIONS Acute (Type I) hypersensitivity ▪ General ▫ Withdraw offending agent, H1 receptor blockers ▪ Anaphylaxis ▫ Hypertension: epinephrine, intravenous fluids, vasopressors (e.g. dopamine) ▫ Bronchoconstriction: nebulized B2 agonists (e.g. salbutamol) ▫ Late-phase reaction, corticosteroids Type II–IV hypersensitivity ▪ Immunosuppression SURGERY Type II–IV hypersensitivity ▪ Irreversible organ damage/rejection → transplant of new organ OSMOSIS.ORG 205
OTHER INTERVENTIONS Type II–IV hypersensitivity ▪ Support organ function HYPERSENSITIVITY PNEUMONITIS osms.it/hypersensitivity-pneumonitis PATHOLOGY & CAUSES ▪ AKA (extrinsic) allergic alveolitis ▪ Reaction to antigens usually 1–5 micrometers in size; fungal, bacterial, mycobacterial, animal, chemical sources ▫ Type III (antibody complex mediated) and IV hypersensitivity (delayed cellmediated) ▫ Inhaled antigen → forms haptens → inflammation of alveoli, small distal airways within lung ▫ Histological changes: inflammation of bronchi, peribronchiolar tissue; diffuse interstitial inflammatory infiltrate; poorly defined granulomas, associated giant cells within lung interstitium/alveoli ▫ Long-standing disease → pulmonary fibrosis, emphysematous changes → ↓ lung capacity, alveolar gas exchange → hypoxemia ▪ > 200 common causative agents identified, often given eponymous names (e.g. farmer’s lung, bird fancier’s lung, etc.) RISK FACTORS ▪ Farming, ventilation, water-related exposure; poultry, bird handling; veterinary work, animal handling; grain, flour processing; grain dust; mold contamination; milling, construction; plastic manufacturing; painting; electronics industry, other chemical industries; textile workers 206 OSMOSIS.ORG SIGNS & SYMPTOMS Acute ▪ Fever, chills, malaise, cough, chest tightness, dyspnea, rash, headache ▪ Resolves 12 hours to several days after cessation of exposure Sub-acute ▪ Productive cough, dyspnea, fatigue, anorexia, weight loss, pleurisy, mild hypoxemia ▪ Lesser severity, longer duration ▪ Resolves weeks to months after cessation of exposure Chronic ▪ Insidious onset cough, progressive dyspnea, fatigue, weight loss, clubbing, tachypnea, respiratory distress, inspiratory crackles (lower lung fields) ▪ Emphysematous component ▪ May have irreversible component, even if antigen removed DIAGNOSIS DIAGNOSTIC IMAGING Bronchoscopy/bronchoalveolar lavage ▪ Marked lymphocytosis; ↑ IgG, IgA, IgM Chest X-ray ▪ Subacute hypersensitivity ▫ Micronodular/reticular opacification in middle to lower lung zones ▪ Chronic hypersensitivity ▫ Progressive fibrotic changes, loss of lung volume (esp. upper lobes)
Chapter 33 Hypersensitivity Reactions: Multiple Mechanisms High-resolution chest CT scan ▪ Subacute hypersensitivity ▫ Diffuse micronodules, ground-glass opacification, focal air trapping/ emphysematous changes, mild fibrosis ▪ Chronic hypersensitivity ▫ Interstitial inflammation, alveolar destruction, dense fibrosis, features of emphysema (centrilobular nodules), ground glass opacification, subpleural honeycombing Figure 33.1 A high resolution CT scan in the axial plane of an individual with hypersensitivity pneumonitis. There are multiple centrilobular ground glass nodules and anterior subpleural reticulation. LAB RESULTS ▪ Lung biopsy ▫ Loose, poorly-defined noncaseating granulomas in vicinity of small airways ▫ Focal fibrotic changes ▪ Immunoassay ▫ Detect antibodies against specific antigens ▫ Chemical labels accumulate in response to specific antigen-antibody reactions/ enzymes bind to specific markers → catalyze color-changing reaction ▫ Known antigens: identify specific antibodies in blood sample OTHER DIAGNOSTICS Diagnostic criteria: acute hypersensitivity ▪ Definite hypersensitivity pneumonitis: 2 and 3, plus one other ▪ Probable disease: 1, 2A, 3 ▪ Subclinical disease: 1, 3A ▪ Previous sensitization: 1 only 1. Known exposure ▪ History of exposure ▪ Aerobiological/microbiological investigation of environment → confirmed exposure ▪ Specific IgG antibodies against identified antigen 2. Compatible clinical, radiographic, physiologic evidence ▪ Respiratory signs: crackles, weight loss, cough, breathlessness, fever, wheezing fatigue, esp. hours after exposure ▪ Radiographic: reticular, nodular, ground glass pattern ▪ Lung function: spirometry (restrictive, obstructive, mixed); diffusion capacity for carbon monoxide (reduced, altered gas exchange) 3. Bronchoalveolar lavage ▪ Lymphocytosis ▪ Positive specific immune response to antigen 4. Inhalation challenge testing ▪ Worsening clinical condition after exposure to environment ▪ Worsening clinical condition after exposure to specific antigen in hospital setting 5. Histopathology ▪ Poorly formed noncaseating granulomas ▪ Mononuclear cell infiltrate Lung function ▪ Subacute ▫ Restrictive pattern ▪ Chronic ▫ Restrictive pattern, hypoxemia at rest, desaturates with exercise, ↓ carbon monoxide diffusion capacity OSMOSIS.ORG 207
TREATMENT MEDICATIONS ▪ Glucocorticoids ▫ Subacute, chronic hypersensitivity ▪ Immunosuppression ▫ Refractory disease SURGERY ▪ Lung transplant ▫ Advanced chronic lung disease OTHER INTERVENTIONS ▪ Identify allergen, reduce/eliminate exposure → disease generally self-limiting (if acute) ▪ Occupational measures ▫ Reduce antigenic burden, moisture control, ventilation, personal protective devices (respirator masks) Figure 33.2 A section of the lung of an individual with hypersensitivity pneumonitis. The alveolar septa are thickened and contain numerous lymphocytes. TRANSPLANT REJECTION osms.it/transplant-rejection PATHOLOGY & CAUSES ▪ Transplanted tissue rejected (attacked) by new host’s immune system → destruction of transplanted tissue Timescale of rejection ▪ Hyperacute rejection ▫ Minutes after transplant ▫ Initiated by humoral immunity ▫ If tissue left implanted → systemic inflammatory response syndrome ▫ Often caused by preexisting anti-human leukocyte antibodies (HLA) ▪ Acute rejection ▫ Highest risk window one week to three months after transplant ▫ Mediated by cellular immunity ▫ Occurs in nearly all transplants if recipient inadequately immunosuppressed 208 OSMOSIS.ORG ▫ Highly vascularised tissue (e.g. kidney, liver) esp. vulnerable ▫ Can be treated prior to organ failure; multiple episodes → chronic rejection ▪ Chronic rejection ▫ Months to years after transplantation ▫ Fibrosis of blood vessels → long term loss of function in transplanted organs Multiple divisions of immune system involved in rejection ▪ Innate immunity → attraction, activation of phagocytes ▪ Humoral immunity → activation of B cells → antibody secretion ▪ Adaptive response → cellular immunity → killer T cells induce apoptosis Cellular markers influencing rejection ▪ Blood group, major histocompatibility (MHC) antigens ▫ Most intense graft rejection reactions
Chapter 33 Hypersensitivity Reactions: Multiple Mechanisms (hyperacute rejection) occur due to differences between donor, recipient ABO blood-groups, MHC antigens ▫ Blood-group antigens expressed on red blood, epithelial, endothelial cells → donor, recipient must be ABO compatible ▫ Minor blood group exposure (e.g. Kell antigen) following allogeneic blood transfusion/trauma during pregnancy may also prime recipient’s humoral immunity against future transplants ▫ MHC compatibility assessed via molecular assay using sequencespecific primers (“tissue typing”) → determination of which HLA alleles expressed by donor, recipient STAGING ▪ Of acute graft rejection Sensitization ▪ Recipient antigen-reactive lymphocytes proliferate in response to alloantigens on graft ▪ Dendritic cells migrate to peripheral lymphoid tissue → present donor’s “self” peptides to recipient’s lymphocytes → presentation of antigen to T cells (helper, killer subclasses), B cells → specific immunity directed at donor self peptides/ ▫ Presence of preformed antibodies to HLA alloantigens must be evaluated to reduce risk of rejection ▪ Minor histocompatibility locus ▫ Short variable proteins, 9–12 amino acids in length, bound to MHC class I, II proteins ▫ Provoke less vigorous immune response, may still lead to slow graft rejection ▫ Potential for graft rejection even if ABO, MHC antigens match ▪ Donor cell debris ▫ Damage-associated molecular patterns by pattern recognition receptors (e.g. toll-like receptors on phagocytes) → further secretion of proinflammatory cytokines, phagocyte chemotaxis donor major histocompatibility complex/ both ▪ CD4+ (T helper), CD8+ (T killer) T cells recognize alloantigen (major, minor histocompatibility complex) on foreign graft cells → proliferation ▫ Direct presentation: donor MHC directly recognised as foreign ▫ Indirect presentation: donor peptides residing in cleft of recipient MHC recognised ▪ T helper (Th) cells activate when they interact with antigen presenting cells OSMOSIS.ORG 209
(APCs) that express appropriate antigenicligand/MHC-molecule complex, provide costimulatory signal ▫ Dendritic cells found in most tissue, express high levels of class II MHC → activated dendritic cells mediate direct presentation in grafts/draining lymph nodes ▫ APCs of host origin migrate into grafts, endocytose foreign alloantigens → indirect presentation of alloantigen ▫ Langerhans, endothelial cells present alloantigen to recipient’s immune system Effector phase ▪ Influx of immune cells into graft ▪ Most common rejection mechanism: cell mediated immunity ▪ Less common: antibody-mediated complement lysis, antibody-dependent cellmediated cytotoxicity ▪ Th cell cytokines play central role → Th1 cells secrete interleukin (IL) 2, interferon (IFN) gamma → T cell proliferation, delayed type hypersensitivity response, IgG synthesis by B cells → complement activation ▪ Cytokines → increased expression of MHC class I, II; IFN, tumor necrosis factor (TNF) ▪ Elevated levels of IL-4, 5, 13, 17 → B-cell activation, eosinophil accumulation within grafts ▪ Antibody-mediated rejection ▫ Antibodies directed against donor HLA molecules/endothelial antigens ▫ Dependent on T cell maintenance of alloreactive B cells → antibody production → activation of complement, deposition of C4d among cells lining graft capillaries TYPES Autograft ▪ Transplant of “self” tissue; surplus tissue that can regenerate/tissue moved from one site to another (e.g. skin, ligament grafts) Isograft ▪ Transplant of tissue between two genetic identical members of same species (e.g. 210 OSMOSIS.ORG transplant between two identical twins) Allograft ▪ Transfer of tissue between genetically non-identical members of same species; non-identical grafts recognised by immune system, destroyed Xenograft ▪ Transplant from one member of species to another (e.g. porcine heart valve transplant) SIGNS & SYMPTOMS ▪ Fever, chills, dizziness, nausea, malaise, night sweats ▪ Specific to transplanted organ: failure of associated organ DIAGNOSIS LAB RESULTS Tissue biopsy ▪ T cell infiltration, accompanied by eosinophils, plasma cells, neutrophils ▪ Structural compromise of tissue anatomy ▪ Blood vessel injury Figure 33.3 A biopsy from a transplanted lung showing a prominent perivascular lymphocytic infiltrate, consistent with rejection. There are numerous background macrophages and eosinophils.
Chapter 33 Hypersensitivity Reactions: Multiple Mechanisms TREATMENT MEDICATIONS Generalized immunosuppression ▪ Mitotic inhibitors (antiproliferatives) ▫ Suppression of B, T cell proliferation; antimetabolites, DNA alkylating agents, fungal metabolites (also suppress T-cell cytokine expression) ▪ Corticosteroids ▫ Anti-inflammatory, potent immunosuppressives at higher doses Specific immunosuppression ▪ Targeted to specific antigens ▪ Monoclonal antibodies ▫ Soluble ligands, bind specific cellsurface molecules → can be used to deplete recipient of particular cell population/block specific steps in cellular signalling ▫ Modern monoclonal antibodies carry toxins (e.g. diphtheria) → target cell internalizes toxin → cell death ▫ Cellular markers expressed only by activated T cells kill cell lines activated after transplant ▫ Cytokines targeted as well; neutralized cytokine no longer stimulates target (e.g. costimulatory signals needed to activate T-helper cells) SURGERY ▪ Removal of transplanted tissue (hyperacute rejection) ▪ Bone marrow transplant (acute rejection) ▫ Recipient bone marrow replaced with donor marrow; risk of graft vs host disease ▪ New transplant (chronic rejection) OTHER INTERVENTIONS ▪ Prevent rejection ▫ Total lymphoid irradiation; X-rays eliminate lymphocytes prior to transplant (e.g. bone marrow transplantation) For acute rejection ▪ Extensive immunosuppressive regimens: corticosteroids, calcineurin inhibitors, antiproliferatives, mTOR inhibitors ▪ Antibody-based treatment ▫ Monoclonal anti-IL-2R alpha receptor antibodies (e.g. basiliximab), polyclonal anti-T cell antibodies (e.g. antithymocyte globulin, antilymphocyte globulin), monoclonal anti-CD20 antibodies (e.g. rituximab) OSMOSIS.ORG 211

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