immunopathology workshop cases

• Allergies (peanut): Why has the patient developed this condition?

  Common presentation of severe allergy presenting in childhood

  Genetic risk factors: alleles on for example chromosomes 5 (Th2 cytokine gene cluster) and 6 (MHC) linked to atopic phenotype

  However, unknown as to why allergy is initially triggered in some individuals and at a specific time point in the life course
• Peanut Allergy: What is the immunopathological mechanism in the case?

  Type 1 hypersensitivity to foreign antigen. NOT autoimmune.

  IgE mediated crosslinking of FceRI -> mast cells activate+degranulate, releasing histamine (preformed) and leukotrienes (synthesised de novo) –> smooth muscle contraction and increased vascular permeability. Histamine activates nerve endings to cause itching
• Peanut allergy: what do eosinophils, basophils and Th2 cells do in allergies?

  Eosinophils - recruited and accumulate in chronic disease. Release mediators (MBP), very damaging

  Basophils - allergen-IgG immune complexes cause release platelet-activating factor -> vascular permeability and anaphylactic shock/systemic anaphylaxis (major player in IgG not IgE-mediated anaphylaxis)

  Th2 cell infiltrate in the tissue in chronic allergy, release cytokines (IL-4, IL-5, IL-13)
• what is MBP (mannose-binding protein)?

  Mannan-binding protein (MBP) is a C-type lectin, which binds to carbohydrates on the surface of some microorganisms and kills them through the activation of complement. This complement activation pathway is called the lectin pathway.
• Peanut Allergy: What were the mechanisms behind the tests and treatments?

  Key to identify the allergen to avoid (peanuts).

  Adrenaline - binds adrenergic receptors – critically here b2 receptors on bronchial smooth muscle, causing bronchodilation and preventing asphyxia

  Chlorphenamine - H1 histamine receptor antagonist administered subcutaneously, intramuscularly or intravenously (relief from swelling and itching)

  Hydrocortisone - corticosteroid, suppresses inflammatory response, reduce inflammation in the late phase and chance of a subsequent severe reaction (e.g., anaphylaxis)
• signs and symptoms to look for in allergies?

  Itching

  Swelling

  Airway constriction

  Pulse and blood pressure changes (in anaphylaxis, systemic vasodilation and increased vascular permeability can cause hypovolemic shock)
• type 1 - immediate hypersensitivity (part 1)

  • •Activation of Th2 cells and production of IgE antibody. 
  • Th2 cells secrete cytokines IL-4, IL-5, and IL-13, responsible for immediate hypersensitivity
  • IL-4 and IL-13 stimulate allergen-specific B cells to undergo heavy-chain class switching to IgE
  • IL-5 activates and recruits eosinophils
  • IL-13 stimulates mucus secretion from epithelial cells
  • Th2 cells are often recruited to the site of allergic reactions in response to locally produced chemokines; one of these chemokines, eotaxin, also recruits eosinophils to the same site.
• type 1 - immediate hypersensitivity (part 2)

  • Sensitization of mast cells by IgE antibody. 
  • Mast cells express a high-affinity receptor for the Fc portion of the ε heavy chain of IgE, called FcεRI
  • affinity of the mast cell FcεRI receptor is so high that the receptors are always occupied by IgE
  • These antibody-bearing mast cells are sensitised to react if the specific antigen (the allergen) binds to the antibody molecules
  • Basophils also express FcεRI, may be recruited into tissues, and may contribute to immediate hypersensitivity reactions.
• type 1 - immediate hypersensitivity (part 3)

  • Activation of mast cells and release of mediators
  • When a person who has been sensitised by exposure to an allergen is reexposed to that allergen, the allergen binds to antigen-specific IgE molecules on mast cells
  • Cross-linking of these IgE molecules triggers a series of biochemical signals from the FcεRI receptor that culminate in the secretion of various mediators from the mast cells.
• Myasthenia Gravis: Why has the patient developed this condition?  


  Genetic risk factors: alleles on chromosome 6 (MHC class II) as well as variants in genes that modulate the immune response (e.g., CTLA4 on chromosome 2)

  However, it is often unknown as to why this and other autoimmune diseases are initially triggered in some individuals and at a specific time point in the life course
• What is the immunopathological mechanism in the case?

  • Failure of central and/ or peripheral self-tolerance mechanisms cause an antibody response to self antigens at postsynaptic terminal of neuromuscular junction
  • Plasma cells secrete IgG antibodies (mostly IgG1, but also IgG3 and others) -> bind to nicotinic acetylcholine receptor. Other autoantigens include MuSK and LRP4
  • Antibody binding leads to: internalisation and degradation of receptors; direct blockage of ACh binding; and activation of complement damaging postsynaptic membrane
• Myasthenia Gravis:what is the effect of how autoantibodies interact with Ach-R, etc on the body?


  The consequence is impairment of signalling required to trigger muscle contraction. This may be manifested in ptosis (extraocular muscles; less severe) or difficulty breathing (diaphragm and other respiratory muscles; more severe)
• what type of hypersensitivity is Myasthenia Gravis?

  Type 2 hypersensitivity to self-antigens -> it is an autoantibody
• Myasthenia Gravis: What were the mechanisms behind the tests?

  Diagnosis = looking at the clinical picture (muscle weakness, commonly ocular initially) and then antibody tests (specificity and titre). There is a minor subgroup of seronegative MG
• Pyridostigmine


  Oral anticholinesterase, inhibits breakdown of acetylcholine, increases amount available for signaling. Used for symptomatic control
• Prednisolone

  Glucocorticoid immunosuppressant. Low dose treatment produces significant clinical response in most patients with mild to moderate disease. Suppresses immune response, reducing autoantibody production and consequently muscle degeneration
• Intravenous immunoglobulins (IVIg)


  Neutralise autoreactive antibodies (prevent binding their target) and neutralises cytokines and blocks activating Fc receptors. Used in the situation of a severe acute exacerbation of myasthenia gravis
• Myasthenia GravisAre there specific signs/symptoms to look for in this condition?

  For diagnosis, muscle weakness particularly with repetitive use. Ocular muscles often involved with consequences of double division (diplopia) and droopy eyelids (ptosis). Muscles in face, limbs and trunk can be involved

  Respiratory distress is indicative of myasthenic crisis and is a potentially life threatening exacerbation
• Systemic Lupus Erythematosus: Why has the patient developed this condition?

  • one of the most common autoimmune diseases
  • Genetic risk factors: MHC class II region of chromosome 6; and various other immune related genes (albeit weakly). Certain rare monogenic diseases are associated with SLE, such as C1q deficiency
  • more common in women and non-white populations. Pregnancy is a risk factor for disease flare; and active lupus is associated with pregnancy complications
• systemic lupus erythematosus: What is the immunopathological mechanism in the case?

  Type 3 hypersensitivity to self antigens - an autoimmunity

  Failure of central and/ or peripheral self-tolerance mechanisms cause antibody response to self antigens normally found in cell nucleus – for example dsDNA, histones, and ribonucleoproteins

  Plasma cells secrete IgG antibodies (IgG1, G2 and G3 may all be present) which bind for example to dsDNA released from dying/dead cells -> formation of immune complexes (antigen, antibody, complement) can deposit in vasculature
• which organs can SLE damage?

  Several different organs can be damaged: lupus nephritis progressing to end stage kidney disease; joint inflammation progressing to erosive arthritis; and pleuritis and pericarditis affecting the lung and heart
• systemic lupus erythematosus: What were the mechanisms behind the tests and treatments?

  Diagnosis = clinical picture (skin, joint, kidney, serosa) and presence of anti-nuclear antibodies (usually anti dsDNA is present)
• systemic lupus erythematosus: what is the treatment

  Corticosteroids - immunosuppressives, suppress adaptive immune response and reduce inflammation and tissue injury from immune complex deposition (activation of complement; tissue damage by myeloid cells, etc)

  Belimumab - monoclonal antibody therapy, blocks (binds and neutralises) B cell survival and stimulatory factor BAFF/BLyS causing B cell apoptosis and reduces autoantibody levels
• systemic lupus erythematosus: Are there specific signs/symptoms to look for in this condition?

  • Wide ranging symptoms but rash on the face, and arthritis, are classic presentations
  • The arthritis in the case will have been an early manifestation of SLE. This disease perhaps should have been diagnosed sooner
• Acute lung transplant rejection: Why has the patient developed this condition?

  • Bilateral lung transplant for cystic fibrosis comes with rejection risk
  • Aim for as good matching as possible of major histocompatibility complex antigens (HLA- A, B, C and HLA-DP, DQ, DR). This is usually not complete. (You would also seek ABO compatibility to avoid hyperacute rejection.) The many minor histocompatibility antigens (resulting from polymorphism of other protein coding genes) are not usually in tissue matching
  • acute because it has occurred within weeks of transplantation
• Acute lung transplant rejection: What is the immunopathological mechanism in the case?

  • Type 4 hypersensitivity (driven by T cells). NOT autoimmune as immune response is against harmless alloantigens (from donor therefore foreign to recipient
• Acute lung transplant rejection: outline the process via direct allorecognition


  • Direct allorecognition is central to acute rejection. Donor APC are carried with donor organ present allo-MHC directly to recipient T cells.
  • Allo-MHC I activates cytotoxic CD8 T cells, which will damage the graft.
  • Allo MHC II will activate helper CD4 T cells, which assists cytotoxic T cell response and secrete inflammatory cytokines
• Acute lung transplant rejection: outline the process with indirect allorecognition

  • In indirect recognition, recipient APC phagocytose, process, and present donor antigens to T cells. This is slower, but can result in cytotoxic T cell, helper T cell and also T-dependent antibody responses against the graft
• acute lung transplant rejection: What were the mechanisms behind the treatments?

  • case: patient on triple immunosuppressant regime since transplantation to prevent organ rejection
  • Tacrolimus - calcineurin inhibitor and inhibits activation of T cells
  • Mycophenolate mofetil - inhibits synthesis of guanosine monophosphate and therefore inhibits cell proliferation
  • Prednisolone - corticosteroid and suppresses inflammation and immunity
• Acute lung transplant rejection: tests

  • Bronchoscopy + biopsy or bronchiolar lavage would be performed to look for immune cell infiltration into the graft - and to look for signs of infection. This will help discriminate infection from rejection. Impaired immunity in a patient under immunosuppression results in a much higher risk of serious infection
• Acute lung transplant rejection: Are there specific signs/symptoms to look for in this condition?

  Reduced organ function, pain at the site

  Systemic symptoms of inflammation: fever and flu like symptoms
• Myasthenia gravis

  • characteristic symptom - muscle weakness arising with repeated usage.
  • affects any striated muscle, (cranial nerve supplied ones especially), especially the eye muscles - over 50%
  • present after stressful events — infection or anaesthesia — with weakness that worsens as day progresses or after repeated usage
  • characteristic laboratory finding is circulating AChR antibodies, (nearly 85–90% of patients).
• Myasthenia Gravis

  • ‘classical’ MG occurs between adolescence and the 20s, females predominate
  • some do not have autoantibodies to the AChR and may have muscle specific kinase (MuSK) autoantibodies and have greater bulbar involvement (e.g. problems talking and eating).
  • strong association with other auto-immune disorders
• Myasthenia gravis: Pathology

  Typically, a collection of mononuclear inflammatory cells (lymphocytes, macrophages) near NMJ, with evidence of degeneration of muscle fibres sometimes. Staining for IgG and complement components (C3, C5b6789 complexes) at the NMJ is positive.

  Electron microscopy - widening of post-synaptic cleft.

  Radiologically examination for thymus enlargement - thymic hyperplasia in 60% and associated with lymphoid germinal centres within the thymus, within which B cells and plasma cells make anti-AChR autoantibody

  Thymectomy may improve symptoms.
• Pathogenesis and immunological features

  MG is typified by anti-AChR antibodies and reduced AChRs at motor end-plates. The AchR has four subunits forming a complex (α2βεδ). The α chain, which contains the binding site for ACh and the snake neurotoxin α-bungarotoxin (a venom that causes paralysis), is the target for autoantibodies. 3 mechanisms by anti-AChR antibodies results in loss of receptor:

  • 1. Complement-mediated damage to the end-plate with AChR loss (the main mechanism).
  • 2. Decreased synthesis and increased degradation of AChRs.
  • 3. Antagonist action by receptor blockade (rare).