Allergic Diseases, Autoimmunity, and Transplantation

what are allergic diseases?

immune dysregulation in response to external stimuli (allergic triggers or allergens)

what are autoimmune disorders?

arise from immune system attacking body’s own healthy cells

what is hypersensitivity - type I?

exaggerated IgE-mediated immune response to allergens that develops <1 hour after exposure

what are the allergens involved in hypersensitivity - type I?

pollen, dust mites, foods, medications, or insect venom

what disorders are related to hypersensitivity - type I?

atopic disorders and allergic disorders

what are the two stages of hypersensitivity - type I?

1. sensitization

2. effector

steps to degranulation in hypersensitivity - type I

1. enzyme Der p 1 cleaves occludin in tight junctions and enters mucosa → Der p 1 taken up by DCs for antigen presentation and T-cell priming

2. DC primes T cell in lymph node → Tfh/Th2 cell induces B-cell switch to IgE production

3. IgE specific Der p 1 travels to mucosa → IgE binds to FceRI receptor on mast cell

4. Der p 1-specific IgE binds to mast cell, Der p 1 triggers mast-cell degranulation → mast cell granule contents cause allergic symptoms

mechanismof mast cell degranulation

1. cross-linking of FceRI by allergen recruits and activates the Syk tyrosine kinase

2. Syk phosphorylates LAT, which recruits and activates PLC-y

3. activated PLC-y generates IP3, which causes calcium release from the ER stores

4. cytosolic calcium indices secretion of contents of mast cell’s performed granules

what are the symptoms of hypersensitivity - type I?

• GI → increased peristalsis and secretion leading to diarrhea and vomiting

• Airway → nasal congestion, increased mucus secretion, sneezing, wheezing, coughing

• Blood → increased blood flow and endothelial permeability, increased flow of blood and lymph, hypotension, and anaphylactic shock

what is hypersensitivity - type II?

antibody dependent cytotoxicity - mediated by IgG and IgM antibodies binding to specific cells or tissues → once antibodies attach → activate complement cascade

what are the effector cells in hypersensitivity - type II?

neutrophils, macrophages, killer cells, eosinophils, and mononuclear phagocytes Fc receptor/C3 receptors bind antibody complex

what disorders/diseases are associated with hypersensitivity - type II?

autoimmune hemolytic anemia, transfusion reactions, Rh disease that can occur during pregnancy, Graves’ disease, and Myasthenia Gravis

what are hypersensitivity - type III responses mediated by?

small and medium immune complexes (large ICs get cleared), and antibodies of the IgG and IgM classes which combine with soluble antigen that are not bound to cell surfaces

what are the steps to hypersensitivity - type III responses?

1. immune complexes form

2. complexes deposit on vessel wall or tissues

3. complement and neutrophil activation and inflammation

4. increased permeability → tissue damage

what diseases are associated with hypersensitivity - type IV?

contact dermatitis and gluten-sensitive enteropathy (celiac disease)

what is hypersensitivity - type IV?

delayed-type hypersensitivity that is mediated by T cells and require 3-5 days to develop (cell-mediated immune reaction)

what are the steps to a TB test (hypersensitivity - type IV)?

1. antigen injected into subcutaneous tissue and processed by local APCs

2. Th1 effector cell recognizes antigen and releases cytokines, which act on vascular endothelium

3. recruitment of phagocytes and plasma to site of injection causes visible lesion

how does tolerance impact autoimmunity?

central and peripheral tolerance is breached → autoimmunity not prevented → killing of own cells

what factors could be associated with an autoimmune disorder?

• genetic factors (ie crohn’s, hashimoto’s)

• trauma (ie sympathetic ophthalmia)

• cross-reactivity (ie rheumatic heart disease)

what is an autograft?

own tissue from one site to another → accepted!

what is a syngeneic graft?

tissue/transplant from identical twin → accepted!

what is an allograft?

tissue/transplant from same species → accepted but needs immunosuppressants

what is a xenograft?

tissue/transplant from different species → rejected

what happens when there is mismatched MHC in allograft transplantation?

allograft rejected rapidly due to T cell-mediated anti-graft response with mismatched MHC (predominantly MHC class I antigens)

what happens when there is minor H antigen incompatibility in allograft transplantation?

allograft rejected slowly

what are the targets of the immunosuppressant Alemtuzumab?

anti-CD52 monoclonal antibody used to deplete T cells and other leukocytes before transplantation

what is the immunosuppressant Belatacept?

fusion protein composed of the Fc fragment of a human IgG1 linked to the extracellular domain of CTLA-4

what are the targets of the immunosuppressants Cyclosporin A and Tacrolimus?

inhibit calcineurin and prevent the translocation of nuclear factor of activated T cells (NFAT) to the nucleus

what are the targets of the immunosuppressant Basiliximab?

anti-CD25 antibody that binds to the high-affinity IL-2 receptor and prevents IL-2 signaling

what are the targets of the immunosuppressant Sirolimus?

interferes with activation of mTOR cascade, which is required for differentiation of effector T cells

what are the targets of the immunosuppressants Azathioprine and Mycophenolate?

inhibit the replication and proliferation of activated T cells