Haematology and immunology: Pathology - Hypersensitivity reactions Flashcards by Hannah Meiklejohn

Four types of hypersensitivity reactions

Type I: immediate
Type II: antibody-mediated
Type III: immune complex-mediated
Type IV: cell-mediated

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Briefly describe the immune mechanism involved in type I (immediate) hypersensitivity reactions

Production of IgE antibody leads to immediate release of vasoactive amines and other mediators from mast cells
Later get recruitment of inflammatory cells

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Briefly describe the immune mechanism involved in type II (antibody-mediated) hypersensitivity reactions

Production of IgG and IgM which then binds to antigen on target cell or tissue
Target cell is phagocytosed or lysed by activated complement or Fc receptors
Leukocytes are recruited

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Briefly describe the immune mechanism involved in type III (immune complex-mediated) hypersensitivity reactions

Deposition of Ag-Ab complexes causes complement activation, resulting in recruitment of leukocytes by complement products and Fc receptors
Enzymes and other toxic molecules released

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Briefly describe the immune mechanism involved in type IV (cell-mediated) hypersensitivity reactions

Activated T lymphocytes release cytokines (leading to inflammation and macrophage activation) and also perform direct T cell-mediated cytotoxicity

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What pathologic lesions are seen in type I (immediate) hypersensitivity reactions?

Vascular dilation
Oedema
Smooth muscle contraction
Mucus production
Tissue injury
Inflammation

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What pathologic lesions are seen in type II (antibody-mediated) hypersensitivity reactions?

Phagocytosis and lysis of cells
In some diseases, can get functional derangements without cell or tissue injury

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What pathologic lesions are seen in type III (immune complex-mediated) hypersensitivity reactions?

Inflammation
Necrotising vasculitis (fibrinoid necrosis)

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What pathologic lesions are seen in type IV (cell-mediated) hypersensitivity reactions?

Perivascular cellular infiltrates
Oedema
Granuloma formation
Cell destruction

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Give 3 examples of type I (immediate) hypersensitivity reactions

Anaphylaxis
Allergy
Atopic asthma

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Give 2 examples of type II (antibody-mediated) hypersensitivity reactions

Autoimmune haemolytic anaemia
Goodpasture syndrome

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Give 4 examples of type III (immune complex-mediated) hypersensitivity reactions

SLE
Some forms of glomerulonephritis
Serum sickness
Arthus reaction (post-vaccination)

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Give 6 examples of type IV (cell-mediated) hypersensitivity reactions

Contact dermatitis
Multiple sclerosis
Type I diabetes mellitus
Rheumatoid arthritis
Inflammatory bowel disease
Tuberculosis

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Identify 5 mast cell mediators which produce the vasodilation and increased capillary permeability seen in type I (immediate) hypersensitivity

Histamine
Platelet-activating factor
Leukotrienes (C4, D4, E4)
Neural proteases -> activate complement and kinins
Prostaglandin D2

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Identify 4 mast cell mediators which produce the smooth muscle spasm seen in type I (immediate) hypersensitivity

Leukotrienes (C4, D4, E4)
Histamine
Prostaglandins
Platelet-activating factor

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Identify 3 mast cell mediators which produce the cellular infiltration seen in type I (immediate) hypersensitivity

Cytokines (e.g. chemokines, TNF)
Leukotriene B4
Eosinophil and neutrophil chemotactic factors

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Give 8 examples of diseases caused by type II (antibody-mediated) hypersensitivity, and identify the antigen involved in each

Autoimmune haemolytic anaemia: Rh blood group Ag, I Ag
Autoimmune thrombocytopaenic purpura: platelet membrane proteins (GpIIb:IIIa integrin)
Goodpasture syndrome: GBM (and BM of lung alveoli)
Acute rheumatic fever: Streptococcal wall Ag cross-reacts with myocardial Ag
Myasthenia gravis: AChR
Graves’ disease: TSH receptor
Insulin-resistant diabetes mellitus: insulin receptor
Pernicious anaemia: intrinsic factor of gastric parietal cells

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Seven important mediators of type I hypersensitivity reactions

Histamine
Proteases (results in increased kinins and activated complement)
Proteoglycans
Leukotrienes B4, C4, D4
Prostaglandin D2
PAF
Cytokines: TNF, IL-1, IL-4, chemokines

Four mechanisms of injury in antibody-mediated hypersensitivity. Explain each in brief

Opsonisation and phagocytosis: IgG coats cells and binds to Fc receptor on phagocytes -> phagocytosis (IgG/IgM activates complement -> opsonisation by C3b or C4a -> phagocytosis or lysis by MAC)
Complement-dependent: direct lysis via C5-9 MAC or by opsonisation-enhanced phagocytosis
Antibody-dependent cell-mediated cytotoxicity: target cells with low concentration of bound IgG/IgE are lysed
Antibody-dependent cellular dysfunction: Ab against cell surface receptors which impair or dysregulate function without injury/inflammation (e.g. anti-AChR in myasthenia gravis, anti-TSH-R in Graves)

Differentiate between systemic and local immune complex disease

Systemic: immune complexes formed in circulation and deposited systemically
Local (Arthus reaction): local tissue vasculitis and necrosis

What pathological changes are seen in acute vs chronic serum sickness?

Acute: vasculitis, activation of complement / platelets / FXIII
Chronic: intimal thickening and scarring

Two mechanisms of cell-mediated hypersensitivity and the mediators of each. Give examples

Delayed-type hypersensitivity: CD4+ TH1 cells secrete cytokines (including IFN-y) in response to Ag, resulting in macrophage activation (seen in TB, fungi, protozoa, parasites, contact dermatitis)
Cell-mediated cytotoxicity: CD8+ T cells bind processed Ag presented on MHC I and induce cell lysis (seen in viral infections, tumours)

NB: both types contribute to transplant rejection

Cellular vs humoral transplant rejection

Cellular: T-cell mediated
Humoral: B-cell mediated

Direct vs indirect pathways in cellular rejection. Which is the major player in acute vs chronic rejection?

Direct: recipient T-cells recognise donor MHC molecules on graft APCs (either in graft tissue or draining lymph nodes), major pathway in acute rejection
Indirect: recipient T-cells recognise donor Ag presented by recipient APCs, major pathway in chronic rejection

Describe the direct pathway in cellular rejection

Recipient T-cells recognise donor MHC molecules on graft APCs CD8+ T-cells kill graft cells, CD4+ T-cells differentiate into TH1 cells and release cytokines to produce delayed hypersensitivity reaction

Describe the indirect pathway in cellular rejection

Recipient T-cells recognise donor Ag presented by recipient APCs Predominant CD4+ T-cell response leading to a delayed hypersensitivity reaction

Pathogenesis of hyperacute vs acute humoral rejection

Hyperacute: due to presence of preformed Abs Acute: new production of Abs after exposure to donor HLA Ags, produces "rejection vasculitis"

Three risk factors for hyperacute rejection

Previous graft rejection Multiparous women (sensitised to paternal HLA Ags) Prior blood transfusions

Describe the timing, pathogenesis and morphology of hyperacute rejection

Timing: minutes to hours Pathogenesis: preformed Abs (prior sensitisation to graft Ag) Morphology: preformed circulating Abs fix to Ags in graft vascular bed, causing endothelial injury leading to thrombosis and fibrinoid necrosis via complement- and ADCC-mediated injury

Which organ is most susceptible to hyperacute rejection? Which is less so?

Most: kidney Less so: liver

Describe the timing, pathogenesis and morphology of acute rejection

Timing: within days in untreated patient, or months to years later if immunosuppression terminated Pathogenesis: may be cellular (T-cell mediated, direct cytotoxicity and delayed hypersensitivity reaction) or humoral (antibody-mediated) Morphology: interstitial mononuclear infiltrate in acute cellular rejection, necrotising vasculitis with thrombosis and infarction in acute humoral rejection

How is acute cellular rejection treated vs acute humoral rejection?

Acute cellular rejection: responds well to immunosuppression Acute humoral rejection: B-cell depleting agents

Describe the timing, presentation and morphology of chronic rejection

Timing: months to years Presentation: progressive renal failure over 4-6 months Morphology: fibrosis and atrophy, interstitial mononuclear infiltrate with plasma cells and eosinophils

Is HLA matching done for all transplant types? Why or why not?

No: often not done for heart, liver or lung due to competing considerations (e.g. anatomic compatibility, illness severity, time to transplant)

What factors impact the amplitude and speed of rejection?

Amplitude affected by degree of genetic disparity Speed increased in highly vascularised tissues

List 5 drugs commonly used for immunosuppression in transplant patients, and briefly outline their mechanism of action

1. Cyclosporine: blocks cytokine transcription factor 2. Azathioprine: inhibits leukocyte development 3. Steroids: block inflammation 4. Mycophenolate mofetil, rapamycin: inhibit lymphocyte proliferation 5. Monoclonal anti-T-cell Ab

What are some of the risks of immunosuppression?

Increased risk of opportunistic infection Increased risk of EBV-induced lymphomas, HPV-induced SCCs, and Kaposi sarcoma

What is graft-versus-host disease?

Complication of haematopoietic stem cell or bone marrow transplantation in which donor cells recognise recipient tissues as foreign

What types of transplant is GVH disease seen in besides bone marrow?

Rarely in transplant of lymphoid-rich solid organs (e.g. liver) or unirradiated blood transfusion

What three conditions are needed to produce GVH disease?

1. Transplant of a graft with functional immune cells 2. Immunologic histo-incompatibility of donor and recipient 3. Recipient immunosuppression

Compare and contrast the timing and clinical presentation of acute vs chronic GVH disease

Acute: occurs within days to weeks, clinical features include rash +/- desquamation, hepatitis with jaundice, and enteritis with bloody diarrhoea Chronic: may follow acute or occur insidiously, clinical features include extensive cutaneous injury (resembling systemic sclerosis), CLD with cholestatic jaundice, GIT injury including oesophageal stricture, thymic involution and lymphocyte depletion, recurrent infection, autoimmunity

Describe the pathogenesis of GVH disease

Graft T-cells are activated by host tissues and release cytokines B-cells are activated by Ag in presence of CD4+ T-cells and start producing Abs to host tissues

How can GVH disease be eliminated? What is the downside?

By donor T-cell depletion prior to transplant However carries increases risk of graft failure, EBV-induced lymphoma, and recurrence of disease in leukaemic patients

What is a possible fatal complication of the immunodeficiency associated with bone marrow transplant?

CMV pneumonitis