IC4

• When the immune mechanisms that defend against microbial infection are excessive, dysregulated, or defective, they give rise to the manifestations of immunological diseases.
• The immune system is necessary to defend against microbial infection.
• Antibodies bind to extracellular antigens, therefore important for defence against extracellular pathogens.
• Effector functions of antibodies include clearance of immune complexes composed of bacteria and Ig by spleen, neutralisation, and T cell help for B cells.
• T cells recognise peptide antigens presented by HLA molecules.
• CD8+ T cells defend against intracellular pathogens, and so there must be mechanisms to display intracellular antigens on the surface of cells.
• Effector functions of T cells include cytotoxic T lymphocytes (effector CD8+ T cells) that kill target cells and helper CD4+ T cells that provide help for other immune cell subsets, such as macrophages, B cells, and even CD8+ T cells.
• The same mechanisms of adaptive immunity that defend against microbial infections can cause tissue damage when they are excessive or aberrant, as seen in hypersensitivity reactions.
• Hypersensitivity reactions are responsive to anti-histamines and may require corticosteroids to control.
• Type I hypersensitivity reactions involve the release of pre-formed mediators by degranulation and de novo transcription of cytokine genes.
• Donor-derived alloreactive CD8+ T cells “contaminating” the HSC graft are responsible for acute GvHD.
• Host versus graft T cell response occurs when HSCT are transplanted into a recipient with some residual functional immunity.
• Activation of donor-derived alloreactive CD8+ T cells damage recipient’s tissues.
• Immunosuppressive drugs are used to suppress graft rejection and GvHD, but they also suppress protective immunity against pathogens and tumour immunosurveillance.
• Encapsulated bacteria are a challenge in HSCT.
• B cells are the last to recover in the neutropaenic phase.
• If residual recipient-derived alloreactive CD8+ T cells reject donor HSCs, it can cause graft rejection and marrow failure.
• Pathophysiology of acute GvHD involves recognition of allogeneic MHC-peptide on recipient APCs by donor-derived mature T cells causing acute GvHD.
• During the neutropaenic phase, there is an increased risk of infection due to low white blood cell counts.
• Neutropaenic phase in HSCT involves bacteria and fungi, and is characterized by a defect in cytotoxicity.
• Graft versus host disease occurs under the following conditions: administration of immunocompetent cells, histo-incompatibility between donor and recipient, and inability of the recipient to destroy or inactivate the transfused cells.
• Host versus graft antibody response involves preformed anti-donor antibodies in the recipient, mainly anti-HLA antibodies and antibodies against blood group antigens, which attack donor cells including HSCs.
• Successful graft in HSCT is indicated by a rise in neutrophil counts about 2 weeks post transplant, but the various lineages take different times to recover.
• Nickel-induced contact dermatitis is an example of a Type IV hypersensitivity reaction produced by a woman's necklace.
• In Type III Hypersensitivity, antibody binds to soluble antigen, cross-linking results in the formation of immune complexes, and large immune complexes precipitate out of solution and deposit in tissues, activating the complement system and recruiting phagocytes.
• Penicillin molecules are too small and structurally simple to generate immune responses by themselves.
• Type IV Hypersensitivity Reactions involve inflammation and tissue damage due to cell-mediated immunity, also known as "Delayed type hypersensitivity" reaction, and involve sensitised T cells (antibodies not involved).
• Individuals who develop IgE-mediated allergic reactions to one β-lactam antibiotic may also react similarly to other compounds in the same class.
• Examples of Type II Hypersensitivity include blood transfusion reactions and penicillin-induced haemolysis.
• Antimicrobial effector functions of T cells include cytotoxic T lymphocytes (effector CD8+ T cells) that kill virus infected cells and helper CD4+ T cells that provide help for other immune cell subsets.
• Examples of Type IV hypersensitivity reactions include tuberculin reactions and oral lichenoid reactions to dental restoration materials.
• Type II Hypersensitivity Reactions involve inflammation and tissue injury triggered by antibody binding to antigen on the surfaces of cells and the activation of complement.
• Cross-allergy to other β-lactam antibiotics occurs due to a common b-lactam ring structure shared by b-lactam antibiotics.
• Cross-reacting anti-penicillin antibodies bind to this molecular motif, triggering an immune response.
• Type III Hypersensitivity Reactions involve inflammation and tissue injury arising from the deposition of antibody-antigen immune complexes in tissues.
• Type I hypersensitivity reactions include urticaria, dermatographism, oedema, peri-oral oedema, angioedema, laryngeal oedema, and anaphylaxis, which is an allergic reaction that is severe and potentially life-threatening.
• Anaphylaxis manifestations include shortness of breath, difficulty breathing, hypotension, and tachycardia.
• Common precipitants of anaphylaxis include insect stings and drugs such as penicillin.
• Penicillin can form a hapten-carrier conjugate with self-protein, which can then act as an immunogen to generate anti-penicillin antibodies.
• Chronic rejection occurs months or years following transplant and is possible due to alloreactive recipient CD4+ T cells activated by indirect allorecognition entering the graft together with recipient APCs.