Haematology and immunology: Pathology - Hypersensitivity reactions Flashcards
Four types of hypersensitivity reactions
Type I: immediate
Type II: antibody-mediated
Type III: immune complex-mediated
Type IV: cell-mediated
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
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
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
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
What pathologic lesions are seen in type I (immediate) hypersensitivity reactions?
Vascular dilation
Oedema
Smooth muscle contraction
Mucus production
Tissue injury
Inflammation
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
What pathologic lesions are seen in type III (immune complex-mediated) hypersensitivity reactions?
Inflammation
Necrotising vasculitis (fibrinoid necrosis)
What pathologic lesions are seen in type IV (cell-mediated) hypersensitivity reactions?
Perivascular cellular infiltrates
Oedema
Granuloma formation
Cell destruction
Give 3 examples of type I (immediate) hypersensitivity reactions
Anaphylaxis
Allergy
Atopic asthma
Give 2 examples of type II (antibody-mediated) hypersensitivity reactions
Autoimmune haemolytic anaemia
Goodpasture syndrome
Give 4 examples of type III (immune complex-mediated) hypersensitivity reactions
SLE
Some forms of glomerulonephritis
Serum sickness
Arthus reaction (post-vaccination)
Give 6 examples of type IV (cell-mediated) hypersensitivity reactions
Contact dermatitis
Multiple sclerosis
Type I diabetes mellitus
Rheumatoid arthritis
Inflammatory bowel disease
Tuberculosis
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
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
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
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
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
- Cyclosporine: blocks cytokine transcription factor
- Azathioprine: inhibits leukocyte development
- Steroids: block inflammation
- Mycophenolate mofetil, rapamycin: inhibit lymphocyte proliferation
- 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?
- Transplant of a graft with functional immune cells
- Immunologic histo-incompatibility of donor and recipient
- 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
