Complement Activation and Regulation
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Questions and Answers

What is the primary role of antibodies in humoral immunity?

  • To produce cytokines that enhance immune responses
  • To activate T cells for cell-mediated immunity
  • To neutralize and eliminate infectious microbes and toxins (correct)
  • To increase the production of blood cells

    • Where are antibodies primarily produced in the body?

  • In the spleen and liver
  • In the skin and mucosal tissues
  • In the thymus and lymph nodes
  • In peripheral lymphoid organs and bone marrow (correct)

    • How do antibodies neutralize the infectivity of microbes?

  • By degrading their cellular structures
  • By blocking their interaction with host cell receptors (correct)
  • By stimulating their apoptosis
  • By enhancing their replication processes

    • What mediates the effector functions of antibodies?

    <p>The Fc regions of immunoglobulin molecules</p> Signup and view all the answers

    What is one mechanism by which opsonized particles are phagocytosed?

    <p>Through the binding of Fc portions to phagocyte Fc receptors</p> Signup and view all the answers

    What is a consequence of insufficient regulation of complement activation?

    <p>Damage to normal cells and tissues</p> Signup and view all the answers

    Which step is targeted by regulatory mechanisms to control complement activation?

    <p>Formation of C3 convertases</p> Signup and view all the answers

    What is a characteristic feature of Paroxysmal nocturnal hemoglobulinuria (PNH)?

    <p>Deficiency of DAF and CD59</p> Signup and view all the answers

    How does the absence of CD59 contribute to PNH symptoms?

    <p>It leads to recurrent thrombosis</p> Signup and view all the answers

    What is a common treatment for the iron loss associated with PNH?

    <p>Administration of iron supplements</p> Signup and view all the answers

    What condition is caused by a deficiency of C1 INH?

    <p>Hereditary angioneurotic edema (HANE)</p> Signup and view all the answers

    What is the role of eculizumab in treating PNH?

    <p>Block the activation of C5</p> Signup and view all the answers

    What characterizes the clinical episodes of hereditary angioedema (HANE)?

    <p>Localized edema primarily on the face, tongue, and larynx</p> Signup and view all the answers

    Which treatment is commonly used for hereditary angioedema?

    <p>Oral androgens and antifibrinolytic agents</p> Signup and view all the answers

    In cases of acquired C1 inhibitor deficiency, what treatment is effective?

    <p>Glucocorticosteroids</p> Signup and view all the answers

    Which deficiency is associated with the highest risk of neisserial infections?

    <p>C2 synthesis defect</p> Signup and view all the answers

    What is the role of meningococcal vaccination in complement deficiencies?

    <p>To create high levels of protective antibodies</p> Signup and view all the answers

    Which complement deficiency is associated with recurrent respiratory infections?

    <p>C3 deficiency</p> Signup and view all the answers

    What triggers the classical pathway of complement activation?

    <p>Antigen-antibody complexes</p> Signup and view all the answers

    Which component is implicated in the life-threatening condition of meningitis due to complement deficiencies?

    <p>Properdin</p> Signup and view all the answers

    How do the major pathways of the complement system converge?

    <p>Through the formation of a membrane pore after C5 cleavage</p> Signup and view all the answers

    What pathway of complement activation is initiated by circulating lectins binding to carbohydrates on pathogens?

    <p>Lectin pathway</p> Signup and view all the answers

    What does immunogenicity refer to in relation to therapeutic proteins?

    <p>The host immune response against a therapeutic protein</p> Signup and view all the answers

    What is a common consequence of the formation of Anti-Drug Antibodies (ADA)?

    <p>Neutralization of drug activity</p> Signup and view all the answers

    Which factor makes predicting and mitigating immunogenicity particularly challenging?

    <p>The incidence of immunogenicity varies from 0% to nearly 50%</p> Signup and view all the answers

    How is immunogenicity information typically presented in the labels of biotherapeutics?

    <p>Stratified by ADA status alongside pharmacokinetics and efficacy</p> Signup and view all the answers

    Which mechanism is NOT associated with the effects of immunogenicity on safety and efficacy?

    <p>Inhibiting immune surveillance</p> Signup and view all the answers

    What is primarily reduced by the co-exposure of FVIII and phosphatidylserine?

    <p>ADA development only against FVIII</p> Signup and view all the answers

    What is a necessary condition for robust tolerance induction in the co-delivery of antigen and drug?

    <p>Co-encapsulation of rapamycin and antigen</p> Signup and view all the answers

    What effect does rapamycin have in the context of immune response?

    <p>Blocks T and B cell activation</p> Signup and view all the answers

    What is a noted consequence of the increased generation of regulatory T cells?

    <p>Reduced activation of memory B cells</p> Signup and view all the answers

    What effect does decreased dendritic cell activation have on the immune system?

    <p>Reduced recognition of FVIII</p> Signup and view all the answers

    What is the dosage range of low dose methotrexate used as an anti-inflammatory agent in rheumatoid arthritis?

    <p>15-17.5 mg/wk</p> Signup and view all the answers

    Which of the following agents is NOT mentioned as reducing ADA development against adalimumab?

    <p>Nonsteroidal anti-inflammatory drugs</p> Signup and view all the answers

    What effect does low dose methotrexate have when used with adalimumab?

    <p>Reduces ADA incidence</p> Signup and view all the answers

    How do T cell epitopes influence immunogenicity?

    <p>Higher content of T cell epitopes increases immunogenicity</p> Signup and view all the answers

    What is the primary purpose of in silico tools in the context of immunogenicity?

    <p>To identify potential immunogenicity liabilities</p> Signup and view all the answers

    What is a downside of long-term treatment with immunosuppressive agents?

    <p>Not desirable due to potential complications</p> Signup and view all the answers

    Which of the following statements about methotrexate is true?

    <p>It reduces ADA development when combined with adalimumab.</p> Signup and view all the answers

    Which class of drugs has been shown to also reduce ADA development besides methotrexate?

    <p>Corticosteroids</p> Signup and view all the answers

    What is the relationship between T cell epitopes and immunogenicity risk?

    <p>More epitopes increase risk.</p> Signup and view all the answers

    What is a common reason for combining antirheumatic drugs like methotrexate with biologics like adalimumab?

    <p>To improve efficacy and reduce immunogenicity</p> Signup and view all the answers

    What is the role of the skin and mucosal surfaces in the immune system?

    <p>They form barriers against infection.</p> Signup and view all the answers

    Which best describes the function of M cells in the gastrointestinal immune system?

    <p>They transport antigens to gut-associated lymphoid tissues.</p> Signup and view all the answers

    What distinguishes primary lymphoid organs from secondary lymphoid organs?

    <p>Primary organs are involved in the generation of mature lymphocytes.</p> Signup and view all the answers

    Which component of the gastrointestinal innate immune system acts as a physical barrier?

    <p>The epithelial cell layer</p> Signup and view all the answers

    How are the gut-homing properties of intestinal lymphocytes developed?

    <p>Through differentiation in lymphoid tissues.</p> Signup and view all the answers

    What type of cells in the intestinal mucosa are responsible for the differentiation of Th17 effector T cells?

    <p>Dendritic cells</p> Signup and view all the answers

    Which cytokine is involved in promoting the differentiation of regulatory T cells in the intestine?

    <p>Transforming growth factor-β</p> Signup and view all the answers

    What is a key function of keratinocytes in the epidermis?

    <p>Producing antimicrobial peptides</p> Signup and view all the answers

    Which of the following molecules is involved in directing effector T cells to the skin?

    <p>Cutaneous lymphocyte antigen (CLA)</p> Signup and view all the answers

    What stimulates the production of vitamin D, which is involved in skin-homing properties of effector lymphocytes?

    <p>UVB exposure</p> Signup and view all the answers

    What type of immune cells primarily take up and process protein antigens from microbes in the gastrointestinal tract?

    <p>Dendritic cells</p> Signup and view all the answers

    Which cytokine is NOT mentioned as being involved in the differentiation of Th17 effector T cells?

    <p>Interleukin-1</p> Signup and view all the answers

    What induces the expression of the chemokine receptor CCR9 on naive B or T cells in GALT?

    <p>Retinoic acid produced by dendritic cells</p> Signup and view all the answers

    What type of interactions occurs between helper T cells and IgM+ B cells during T-dependent IgA class switching?

    <p>Cognate interactions</p> Signup and view all the answers

    What process allows IgA to be transported from the basolateral to the luminal side of epithelial cells?

    <p>Transcytosis</p> Signup and view all the answers

    What role do dendritic cells play in the gastrointestinal immune system?

    <p>They stimulate regulatory T cell responses.</p> Signup and view all the answers

    Which mechanism is NOT involved in IgA class switching?

    <p>Macrophage activation</p> Signup and view all the answers

    Where do plasma cells primarily produce IgA in the body?

    <p>Lamina propria of mucosal tissue</p> Signup and view all the answers

    What type of antigens do dendritic cells in Peyer’s patches capture to activate naive CD4+ T cells?

    <p>Bacterial antigens only</p> Signup and view all the answers

    What is the role of the poly-Ig receptor in the transport of IgA?

    <p>It binds to IgA for transcytosis.</p> Signup and view all the answers

    What occurs during central tolerance when immature lymphocytes recognize self antigens?

    <p>They undergo deletion or change their specificity.</p> Signup and view all the answers

    What is the role of the AIRE protein in T cell tolerance?

    <p>It regulates the expression of peripheral tissue antigens in the thymus.</p> Signup and view all the answers

    Which mechanism is NOT a part of peripheral tolerance?

    <p>Activation by cytokines</p> Signup and view all the answers

    What is the primary consequence of negative selection in the thymus?

    <p>It deletes immature T cells that recognize self antigens.</p> Signup and view all the answers

    Which type of lymphocyte specifically develops into regulatory T cells during central tolerance?

    <p>CD4+ T cells</p> Signup and view all the answers

    What occurs when T cells recognize self antigens without costimulation?

    <p>They may become anergic.</p> Signup and view all the answers

    Which statement correctly describes the role of CTLA-4 in T cell activation?

    <p>CTLA-4 competes with CD28 for B7 ligands.</p> Signup and view all the answers

    Which cytokine is primarily produced by regulatory T cells to suppress immune responses?

    <p>Transforming Growth Factor-β (TGF-β)</p> Signup and view all the answers

    What mechanism does CTLA-4 utilize to inhibit T cell activation?

    <p>Inhibiting signal transduction from CD28.</p> Signup and view all the answers

    How does TGF-β1 contribute to immune modulation?

    <p>It inhibits T cell proliferation and effector functions.</p> Signup and view all the answers

    What effect do anergic T cells exhibit in response to antigen stimulation?

    <p>They show a diminished response.</p> Signup and view all the answers

    What is a key function of regulatory T cells in immune responses?

    <p>Suppressing the activity of dendritic cells.</p> Signup and view all the answers

    Which protein is targeted for degradation when TCR signaling is inhibited in anergic T cells?

    <p>TCR-associated proteins.</p> Signup and view all the answers

    What is the primary function of Interleukin-10 (IL-10) in the immune response?

    <p>Inhibits activated macrophages and dendritic cells</p> Signup and view all the answers

    Which statement accurately describes tolerogenic antigens?

    <p>They are associated with unresponsiveness in immature lymphocytes.</p> Signup and view all the answers

    What happens to immature B lymphocytes that recognize self antigens with high affinity?

    <p>They are deleted or change their specificity.</p> Signup and view all the answers

    What is central tolerance in the context of B cells?

    <p>The deletion of high-affinity self antigen-reactive immature B lymphocytes.</p> Signup and view all the answers

    Which condition is likely to result from the failure of self-tolerance in the immune system?

    <p>Development of autoimmune diseases</p> Signup and view all the answers

    How does IL-10 affect T cell activation?

    <p>It terminates cell-mediated immune reactions.</p> Signup and view all the answers

    What type of immune tolerance is characterized by recognizing self antigens in peripheral tissues?

    <p>Peripheral tolerance</p> Signup and view all the answers

    What is one major way B cells contribute to autoimmune conditions?

    <p>By secreting pro-inflammatory cytokines</p> Signup and view all the answers

    Which mechanism does Rituximab use to reduce B cell populations?

    <p>Direct lysis and antibody-dependent cellular cytotoxicity</p> Signup and view all the answers

    What is a consequence of using B cell depleting monoclonal antibodies in autoimmune therapy?

    <p>Potential reduction of B cell-dependent autoimmunity</p> Signup and view all the answers

    Which type of diseases have B cell depleting antibodies primarily been developed to treat?

    <p>B cell malignancies</p> Signup and view all the answers

    What distinguishes the use of B cell depleting antibodies in both autoimmune conditions and malignancies?

    <p>They target only CD20-expressing B cells</p> Signup and view all the answers

    What is a significant effect of anti-TNF treatment in patients with rheumatoid arthritis?

    <p>Reduction in disease severity compared to placebo</p> Signup and view all the answers

    Which of the following is a key advantage of kinase inhibitors compared to biologic treatments?

    <p>Oral availability, eliminating the need for injections</p> Signup and view all the answers

    What is a common side effect associated with approved kinase inhibitors?

    <p>Hypercholesterolemia and infections</p> Signup and view all the answers

    What is the role of cytokine blockade in treating autoimmune conditions?

    <p>Increases susceptibility to viral infections</p> Signup and view all the answers

    Which statement is true regarding the efficacy of TNF blockers?

    <p>Show efficacy in various autoimmune diseases due to TNF signaling</p> Signup and view all the answers

    What is the primary use of intravenous immunoglobulin (IVIG)?

    <p>Immunoglobulin replacement for primary immunodeficiencies</p> Signup and view all the answers

    At what high dose range is IVIG typically used to treat autoimmune conditions?

    <p>1-3 g/kg</p> Signup and view all the answers

    What is a key mechanism by which IVIG acts in autoimmune conditions?

    <p>Direct neutralization of autoantibodies</p> Signup and view all the answers

    What is a significant downside of using IVIG?

    <p>The costs are exceptionally high, often around $10,000 per dose.</p> Signup and view all the answers

    Which of the following is NOT a mechanism through which IVIG is thought to work?

    <p>Direct stimulation of T-cells</p> Signup and view all the answers

    Which condition was IVIG initially developed to treat?

    <p>Primary immunodeficiencies</p> Signup and view all the answers

    What effect does IVIG have on effector mechanisms?

    <p>Biased towards anti-inflammatory responses</p> Signup and view all the answers

    Why are the costs of IVIG treatments considered high?

    <p>It is made from human plasma, which involves complex processes.</p> Signup and view all the answers

    What is the impact of IVIG on pathogenic antibodies?

    <p>It leads to their accelerated elimination.</p> Signup and view all the answers

    Which of the following is a consequence of the plasma-derived nature of IVIG?

    <p>It is subject to supply chain fluctuations and high costs.</p> Signup and view all the answers

    What type of hypersensitivity reaction is unique to allergic diseases?

    <p>Type I hypersensitivity</p> Signup and view all the answers

    What is the effect of autoantibodies that act as receptor agonists?

    <p>They mimic the natural ligand and activate signaling.</p> Signup and view all the answers

    What autoimmune condition is caused by autoantibodies against the TSH receptor?

    <p>Graves’ disease</p> Signup and view all the answers

    What occurs when autoantibodies act as receptor antagonists?

    <p>They block the natural ligand from activating the receptor.</p> Signup and view all the answers

    What describes the mechanism by which antibodies against streptococcal antigens can cause rheumatic fever?

    <p>They cross-react with myocardial antigens due to molecular mimicry.</p> Signup and view all the answers

    Which type of hypersensitivity reaction is associated with autoimmune diseases?

    <p>Type II hypersensitivity</p> Signup and view all the answers

    What is the primary immune response involved in allergic diseases?

    <p>IgE antibody production</p> Signup and view all the answers

    Which mechanism is primarily depended on T cells in hypersensitivity reactions?

    <p>Delayed-type hypersensitivity</p> Signup and view all the answers

    Which of the following statements about hypersensitivity responses is accurate?

    <p>Persistent infections can lead to hypersensitivity as an immune defense mechanism.</p> Signup and view all the answers

    Which characteristic is typical of individuals with sensitivities to environmental antigens?

    <p>They have a failure of self-tolerance mechanism.</p> Signup and view all the answers

    What is the primary consequence of autoantibodies binding to acetylcholine receptors in myasthenia gravis?

    <p>Reduction in receptor availability</p> Signup and view all the answers

    In Graves' disease, thyroid hormone production disregards the body's needs and the role of which hormone?

    <p>TSH</p> Signup and view all the answers

    What role does complement fixation play in autoimmune hemolytic anemia?

    <p>Mediates lysis of opsonized RBCs</p> Signup and view all the answers

    Which mechanism primarily leads to muscle weakness in myasthenia gravis?

    <p>Endocytosis of neurotransmitter receptors</p> Signup and view all the answers

    How do autoantibodies differ from antibodies produced in response to infections?

    <p>Autoantibodies usually arise from autoimmune responses</p> Signup and view all the answers

    What is a potential outcome when antibodies act as antagonists at cell surface receptors?

    <p>Inhibition of receptor function</p> Signup and view all the answers

    In the context of autoimmune diseases, what is a common characteristic of antibodies that cause tissue-specific damage?

    <p>They typically arise from an immune response to self-antigens</p> Signup and view all the answers

    What immune response mechanism is involved in the phagocytosis of opsonized red blood cells in autoimmune hemolytic anemia?

    <p>Fc receptor-mediated phagocytosis</p> Signup and view all the answers

    What effect does the presence of autoantibodies in Graves' disease have on the regulation of thyroid function?

    <p>Creates an unregulated hyperthyroid state</p> Signup and view all the answers

    Which mechanism is NOT involved in the destruction of red blood cells in autoimmune hemolytic anemia?

    <p>Direct antibody-induced apoptosis</p> Signup and view all the answers

    What effect does Interleukin-2 (IL-2) NOT have on T lymphocytes?

    <p>Promotes their differentiation into muscle cells</p> Signup and view all the answers

    What is the primary function of the immune synapse?

    <p>To create a stable interface for TCR signaling</p> Signup and view all the answers

    What is a key consequence of the degradation of signaling proteins in the immune synapse?

    <p>Termination of T cell activation</p> Signup and view all the answers

    Which mechanism is associated with corticosteroids in the immune response?

    <p>Switching on anti-inflammatory gene expression</p> Signup and view all the answers

    What does the immune synapse ensure during T cell signaling?

    <p>Specific delivery of granule contents to target cells</p> Signup and view all the answers

    What is the role of glucocorticoid receptors (GRs) after being activated by corticosteroids?

    <p>To bind coactivators and inhibit HAT activity</p> Signup and view all the answers

    Which process leads to the suppression of activated inflammatory genes by corticosteroids?

    <p>Translocation of HDAC2 to reverse histone acetylation</p> Signup and view all the answers

    What is the effect of histone acetyltransferases (HATs) on gene expression?

    <p>They lead to acetylation of lysines on histone H4</p> Signup and view all the answers

    How do corticosteroids primarily affect the expression of inflammatory genes?

    <p>By inhibiting the transcription factors that activate inflammatory genes</p> Signup and view all the answers

    What is the significance of acetylation of core histone H4 in inflammatory gene expression?

    <p>It enhances the transcription of inflammatory proteins</p> Signup and view all the answers

    What is the primary mechanism behind the rejection of transplanted organs?

    <p>Adaptive immune response mediated by lymphocytes</p> Signup and view all the answers

    Which situation would most likely lead to successful organ transplantation?

    <p>Transplanting between genetically identical individuals</p> Signup and view all the answers

    What typically happens to skin grafts from unrelated donors in burn patients?

    <p>They undergo necrosis and fall off within 1 to 2 weeks</p> Signup and view all the answers

    What experimental observation first highlighted the issue of graft rejection?

    <p>Unsuccessful skin grafting in burn patients</p> Signup and view all the answers

    Which rule of transplantation immunology states that an (A × B) F1 animal will not reject grafts from either parent?

    <p>Grafts from offspring are accepted by the parents</p> Signup and view all the answers

    What is a notable exception to the general rules of graft rejection?

    <p>Hematopoietic stem cell transplantation</p> Signup and view all the answers

    Which factor does NOT influence whether a graft will be rejected?

    <p>Age of the recipient at the time of transplant</p> Signup and view all the answers

    Which statement best describes the outcomes when transplanting organs from different inbred strains?

    <p>Transplants are typically rejected almost universally</p> Signup and view all the answers

    What should be expected when grafts derived from offspring are transplanted into one of the parents?

    <p>The graft will likely be rejected by either parent</p> Signup and view all the answers

    Study Notes

    Complement Activation

    • Low-level complement activation can damage normal cells and tissues.
    • Complement activation, even when needed, should be regulated since degradation products of complement proteins can injure adjacent cells.
    • Regulatory mechanisms include:
      • Inhibition of formation of C3 convertases in early steps.
      • Break down and inactivation of C3 and C5 convertases.
      • Inhibition of the formation of the MAC in the late steps.

    Molecules and Receptors that Inhibit Complement Activation

    • DAF (Decay-Accelerating Factor) and CD59 prevent formation of the MAC on host cells.
    • Factor H and Factor I inhibit complement activation on host cells.
    • C1 inhibitor is a protein that blocks activation of the classical pathway.

    Functions of Complement

    • Opsonizes pathogens and promotes their phagocytosis.
    • Lyses pathogens directly.
    • Recruits inflammatory cells.
    • Clears immune complexes.

    Complement Deficiencies

    • Paroxysmal Nocturnal Hemoglobinuria (PNH)
      • Individuals lack both DAF and CD59.
      • Results in intravascular red cell hemolysis and hematoglobinuria.
      • Absence of CD59 on platelets contributes to recurrent thrombosis.
      • PNH Treatment:
        • Transfusion of red blood cells.
        • Androgens and erythropoietin to accelerate erythropoiesis.
        • Heparin and anticoagulants to treat thrombosis.
        • Iron supplementation.
        • Eculizumab to block C5 activation and MAC generation.
    • Hereditary Angioedema (HANE)
      • Caused by C1 INH deficiency.
      • HANE Treatment:
        • Oral androgens, anabolic steroids, and antifibrinolytic agents.
        • Glucocorticosteroids in acquired C1 INH deficiency.
    • Other Deficiencies:
      • C2 deficiency: Increases risk of neisserial infections.
      • C3 deficiency: Recurrent infections of respiratory tract, gut, and skin.
      • Properdin, Factor H, Factor I, and MAC deficiencies: Life-threatening meningitis.

    Vaccine-Induced Humoral Immunity

    • Vaccines induce antibody production which can neutralize microbes and prevent infections.
    • Vaccines can act through different mechanisms like:
      • Direct neutralization of microbes.
      • Inducing the formation of antibodies that activate complement to lyse microbes.
      • Opsonization of microbes for phagocytosis.

    Functions of Antibody Isotypes

    • IgG
      • Activates complement.
      • Opsonizes microbes for phagocytosis.
      • Antibody-dependent cell-mediated cytotoxicity (ADCC).
      • Crosses the placenta.
    • IgM
      • Activates complement.
      • Opsonizes microbes for phagocytosis.
      • Neutralizes microbes and toxins.
      • First antibody produced during a primary immune response.
    • IgA
      • Found in mucosal secretions like saliva, tears, and gut fluids.
      • Neutralizes microbes and toxins.
      • Prevents attachment of microbes to mucosal surfaces.
    • IgE
      • Involved in allergic reactions.
      • Involved in defense against parasitic infections.
    • IgD
      • Found on surface of naive B cells.
      • Function is not completely understood.

    Neutralization of Microbes and Toxins by Antibodies

    • Antibodies bind to microbes or toxins, preventing their interaction with host cells.
    • This blocks the infectivity of microbes and the pathological actions of toxins.

    Antibody-mediated Opsonization and Phagocytosis of Microbes

    • Antibodies bind to microbes and act as opsonins, making them more susceptible to phagocytosis.
    • Phagocytes have Fc receptors that bind the Fc portion of antibodies and engulf antibody-coated microbes.

    Antibody-Dependent Cell-mediated Cytotoxicity (ADCC)

    • Antibodies bind to microbes and trigger the killing of target cells by NK cells.
    • NK cells express Fc receptors that bind to the Fc portion of antibodies, leading to the release of cytotoxic granules that kill the target cell.

    Humoral Immunity

    • Is mediated by antibodies and is a key part of the adaptive immune response.
    • Primarily responsible for defense against extracellular microbes and their toxins.
    • Antibodies can be generated by long-lived antibody-secreting cells or by reactivation of memory B cells.
    • Antibodies play a crucial role in:
      • Neutralizing microbes and toxins.
      • Opsonization of microbes for phagocytosis.
      • Antibody-dependent cell-mediated cytotoxicity.

    Immunogenicity

    • Immunogenicity describes the host immune response against a therapeutic protein, usually studied in the context of Anti-Drug Antibodies (ADA).
    • All FDA-approved biotherapeutics have a section on immunogenicity (Section 6.2) within the Adverse Reactions section of the label.
    • Immunogenicity incidence varies greatly depending on various drug- and patient-related factors, ranging from 0% to nearly 50% of subjects.
    • The impact of immunogenicity is often displayed graphically in biotherapeutics labels, stratified by ADA status.

    Impact of Immunogenicity

    • ADA can negatively impact both safety and efficacy of biotherapeutics.
    • ADA can neutralize drug activity, accelerate drug elimination, and form immune complexes.
    • This contributes to a reduction in efficacy and safety.

    Strategies to Reduce Immunogenicity

    • Antigen Specificity
      • Co-exposure of Factor VIII with phosphatidylserine can induce immunological tolerance in preclinical models.
      • Tolerance is specific, reducing ADA development only against Factor VIII and not unrelated antigens.
    • Cellular Mechanisms
      • Tolerance induction involves increased generation of regulatory T cells, decreased dendritic cell activation, and reduced memory B cells.
    • Co-Delivery of Antigen and Drugs
      • Co-delivery of immunosuppressive drugs like rapamycin (Sirolimus) with the antigen reduces ADA development.
      • Robust tolerance induction is observed with co-encapsulation of rapamycin and the antigen.
    • Anti-Inflammatory Drugs
      • Low-dose methotrexate reduces ADA development against adalimumab in patients.
      • Methotrexate, frequently used for rheumatoid arthritis, decreases ADA incidence and increases adalimumab serum concentrations when combined with it.
      • Other immunosuppressive agents, like corticosteroids and B-cell depleting agents (e.g., rituximab), have also shown similar effects.

    Predicting Immunogenicity

    • T cell epitopes are peptide sequences recognized by MHC and bind to the T-cell receptor.
    • A molecule with a higher content of T cell epitopes generally has a higher risk of immunogenicity.
    • In silico tools are available to identify potential immunogenicity liabilities based on T-cell and B-cell epitopes and help "de-risk" molecules.

    Tolerance Restoration

    • Clinically used protocols to restore tolerance include the:
      • Bonn Protocol
      • Van Creveld Protocol
      • Malmo Protocol
    • The mechanisms behind these protocols are not fully understood, but they aim to suppress ADA response by constant exposure to the antigen under non-inflammatory conditions.

    Defining Immune Tolerance

    • Immune tolerance refers to the prevention of an immune response to a specific antigen.
    • Tolerance is antigen-specific, meaning tolerance to one protein shouldn't affect responses to unrelated drugs.
    • Tolerance should involve cellular responses, not just ADA depletion, including decreased dendritic cell maturation, increased regulatory T cells, and decreased memory B cells.

    Maintenance of Self-Tolerance

    • Apoptosis (programmed cell death) is crucial for maintaining self-tolerance and preventing autoimmunity.
    • Phosphatidylserine, normally confined to the inner leaflet of cell membranes, is exposed during apoptosis and triggers engulfment by phagocytes promoting tolerance.

    Apoptotic Mimicry to Induce Tolerance

    • Co-exposure of a therapeutic protein and phosphatidylserine can promote a tolerogenic response.

    Clinical Trial - Nanoparticle Co-Delivery of Antigen/Rapamycin

    • Pegloticase, a PEGylated uricase used to treat gout, is highly immunogenic.
    • Clinical trials using nanoparticles encapsulating pegloticase and rapamycin, demonstrated:
      • Reduced ADA development against pegloticase.
      • Improved disease severity by allowing sustained pegloticase treatment.

    Summary

    • Immunogenicity can negatively affect PK, safety, and efficacy of biologics (proteins, cell and gene therapies).
    • ADA can be “neutralizing” or “binding”.
    • Immunogenicity prediction in individuals is challenging due to numerous factors.
    • Tolerance induction should be antigen-specific and involve immune system cellular components.

    Barrier Immune System

    • The skin and mucosal surfaces form the barrier immune system, which is technically considered a component of the innate immune system.
    • These structures provide a physical barrier to infection, preventing pathogens from entering the body.

    Lymphoid Tissues

    • Lymphoid tissues are classified as generative organs (primary or central) or peripheral organs (secondary).
    • Generative organs are where lymphocytes first express antigen receptors and mature.
    • Peripheral organs are where lymphocyte responses to foreign antigens are initiated and develop.

    Gastrointestinal Immune System

    • The gastrointestinal system is composed of a tube-like structure lined by a continuous epithelial cell layer sitting on a basement membrane, serving as a physical barrier.
    • The gastrointestinal system contains specialized lymphoid tissues like MALTs (mucosa-associated lymphoid tissues) and Peyer's patches.
    • Intestinal epithelial cells are part of the innate immune system, responding to pathogens and sampling antigens for the adaptive immune system.

    M Cells

    • M cells are located in follicle-associated epithelium, overlying Peyer's patches and other GALT structures.
    • These cells are specialized for antigen uptake from the gut lumen and delivery to the GALT.
    • M cells are distinguishable by a thin glycocalyx, short, irregular microvilli, and large fenestrations in their membranes, all features that enhance antigen uptake.

    Homing Properties of Intestinal Lymphocytes

    • Effector lymphocytes in the gut are imprinted with homing properties in the lymphoid tissues where they differentiate.
    • Dendritic cells in GALT induce expression of the chemokine receptor CCR9 and the integrin α4β7 on effector lymphocytes.
    • This imprinting directs the effector lymphocytes back to the gut lamina propria.

    IgA Class Switching in the Gut

    • IgA class switching in the gut occurs by both T-dependent and T-independent mechanisms
    • In T-dependent IgA class switching, dendritic cells capture antigens and present them to naive CD4+ T cells, which differentiate into T follicular helper cells.
    • These helpers engage with antigen-presenting IgM+ B cells, ultimately leading to IgA class switching.

    Transport of IgA Across Epithelial Cells

    • IgA produced by plasma cells in the lamina propria binds to the poly-Ig receptor at the base of an epithelial cell.
    • This complex is transported across the epithelial cell and released into the lumen.
    • This process, from the basolateral to the luminal surface, is called transcytosis.

    Antigen Sampling by Intestinal Dendritic Cells

    • DCs and macrophages in the gastrointestinal system stimulate protective effector T cell responses or induce regulatory T cell responses.
    • DCs take up and process antigens from microbes in the lumen or those breaching the epithelial barrier.
    • DCs transport these antigens via lymphatics to mesenteric lymph nodes.

    Effector and Regulatory T Cells in the Intestinal Mucosa

    • Different subsets of effector CD4+ T cells are induced by and protect against different microbial species.
    • Th17 effector T cells and regulatory T cells are abundant in the intestinal mucosa.
    • Bacterial antigen-specific Th17 cells differentiate in response to antigens presented by DCs and cytokines like IL-6 and IL-23.
    • Regulatory T cell differentiation is promoted by TGF-β and retinoic acid produced by intestinal epithelial cells.

    The Cutaneous Immune System

    • The epidermis forms a physical barrier to microbial invasion, composed of multiple layers of stratified squamous epithelium.
    • Keratinocytes, the main cells in the epidermis, respond to pathogens and injury by producing antimicrobial peptides and cytokines.

    Homing Properties of Cutaneous Lymphocytes

    • Skin-homing properties of effector lymphocytes are imprinted in skin-draining lymph nodes.
    • UVB rays induce Vitamin D expression, IL-12 induces CLA expression, and other signals induce CCR4, CCR8, and CCR10 expression.
    • These molecules direct migration of effector T cells into the skin.

    Immune-Privileged Tissues

    • Immune responses and inflammation in certain tissues like the brain, eye, testes, placenta, and fetus carry high risks.
    • These tissues are called immune-privileged sites, evolved to be protected from immune responses to varying degrees.

    Immune Privilege in the Testis

    • Immune privilege in the testis limits inflammation that may impair male fertility.
    • Many self antigens in the adult testis were expressed after the immune system developed, making it unlikely for lymphocytes targeting these antigens to be deleted.
    • Immune privilege in the testis likely prevents autoimmunity.

    Immune Privilege in the Fetus

    • The fetus expresses paternally inherited genes, which are foreign to the mother.
    • Maternal antibodies against paternal MHC molecules are easily detectable during pregnancy.
    • Placental features and local immunosuppression contribute to fetal immune privilege.

    Tolerance to Self Antigens

    • Tolerance to self antigens is a fundamental property of the immune system that prevents autoimmune diseases.
    • Two mechanisms are involved: central tolerance and peripheral tolerance.

    Central Tolerance

    • Occurs in generative lymphoid organs: thymus for T cells and bone marrow for B cells.
    • Immature lymphocytes are exposed to self antigens, leading to deletion, altered specificity (B cells), or development of regulatory lymphocytes (Tregs, CD4+ T cells).

    Peripheral Tolerance

    • Mature lymphocytes that escape central tolerance may encounter self antigens in peripheral tissues.
    • Mechanisms: anergy (functional unresponsiveness), suppression by Tregs, and deletion.

    Central T Cell Tolerance

    • Mature lymphocytes that encounter self antigens in the thymus undergo negative selection or differentiate into Tregs.
    • Autoimmune regulator (AIRE) protein plays a vital role in expressing numerous peripheral tissue antigens in medullary thymic epithelial cells (MTECs) for negative selection.

    Peripheral T Cell Tolerance

    • Anergy is induced in T cells:
      • Blockage of TCR-induced signal transduction.
      • Ubiquitination of TCR-associated proteins leading to degradation in proteasomes or lysosomes.
      • Engagement of inhibitory receptors, such as CTLA-4 and PD-1.
    • Tregs suppress T cell responses through mechanisms like:
      • Suppressing immune responses at multiple steps, like production of IL-10 and TGF-β.
      • Reducing APC’s ability to stimulate T cells.
      • Consumption of IL-2.
    • Inhibitory cytokines like IL-10 and TGF-β mediate T cell suppression by:
      • Inhibiting activated macrophages and dendritic cells, reducing innate responses.
      • Inhibiting IL-12 production by dendritic cells and macrophages.
      • Inhibiting co-stimulator and MHC II expression on APCs, reducing T cell activation.
      • Inducing IgA antibody production by promoting B cells to switch isotypes.
      • Promoting tissue repair after immune responses subside.

    Factors Determining Immunogenicity vs. Tolerogenicity

    • Tolerogenic antigens are expressed in generative lymphoid organs for immature lymphocytes.
    • Self antigens in peripheral tissues engage antigen receptors for prolonged periods without inflammation or innate immunity.
    • Dendritic cell type plays a crucial role in determining the outcome of the immune response.

    Central Tolerance in B Cells

    • Immature B cells in the bone marrow, encountering self antigens with high affinity, undergo receptor editing (specificity alteration) or deletion (apoptosis).
    • Mature B cells, recognizing self antigens in peripheral tissues without helper T cells, become functionally unresponsive or undergo apoptosis.

    Postulated Mechanisms of Autoimmunity

    • Genetic susceptibility and environmental triggers like infections and tissue injury contribute to autoimmunity.
    • Autoimmune diseases can be systemic or organ-specific depending on the autoantigens involved.
    • Effector mechanisms include immune complexes, circulating autoantibodies, and autoreactive T lymphocytes.
    • Autoimmune diseases are often chronic, progressive, and self-perpetuating.

    Immunologic Abnormalities Leading to Autoimmunity

    • Defective self-tolerance: imbalance between lymphocyte activation and control.
    • Defects in negative selection of T or B cells, or receptor editing in B cells during maturation.
    • Defective numbers or function of regulatory T lymphocytes.
    • Defective apoptosis of mature self-reactive lymphocytes.
    • Inadequate function of inhibitory receptors.
    • Abnormal display of self antigens: increased expression, persistence, or structural changes leading to neoantigens.

    TNF Blockers

    • Anti-TNF therapies have shown significant reduction in rheumatoid arthritis severity compared to placebo
    • These drugs are effective in other autoimmune conditions, highlighting the importance of TNF signaling in autoimmune diseases
    • While effective, TNF blockers can increase risk of infections, cancer, and other adverse effects

    Kinase Inhibitors

    • Kinases play an important role in signal transduction pathways following receptor activation
    • Inhibiting kinases can block signaling from multiple receptors simultaneously
    • Many kinase inhibitors are orally available, offering an advantage over injectable biologics
    • Several kinase inhibitors are approved and in development for the treatment of autoimmune diseases
    • While effective, they can lead to side effects such as infections, high cholesterol, and herpes zoster reactivation

    B Cell Role in Autoimmunity

    • B cells play a significant role in the pathogenesis of numerous autoimmune diseases.
    • B cells contribute to disease through:
      • Production of autoantibodies (plasma cells)
      • Secretion of pro-inflammatory cytokines
      • Antibody-independent effects
    • Modulating B cell function holds potential for treating autoimmune diseases.

    B Cell Depleting Antibodies

    • Anti-B cell monoclonal antibodies (mAbs) are commonly used to treat autoimmune diseases.
    • These mAbs were originally developed to treat B cell malignancies.
    • They target and deplete all cells expressing the specific antigen.
    • Rituximab, a B cell depleting mAb, is used in rheumatoid arthritis patients with inadequate response to anti-TNF therapy.

    Mechanism of Action of B Cell Depleting mAbs

    • Rituximab eliminates CD20-expressing B cells through three mechanisms:
      • Direct lysis
      • Antibody-dependent cellular cytotoxicity
      • Complement-dependent cytotoxicity
    • This reduction in circulating B cells effectively reduces B cell-dependent autoimmunity.

    Intravenous Immunoglobulin (IVIG)

    • Immunoglobulin replacement therapy can be administered intravenously (IVIG) or subcutaneously (SCIG).
    • IVIG was initially developed and is still used to treat primary immunodeficiencies by reconstituting the missing antibody pool.
    • High doses of IVIG (1-3 g/kg) are used to treat autoimmune conditions.
    • IVIG, being a plasma-derived product, is very expensive (~$10,000/dose).

    IVIG Mechanisms in Autoimmunity

    • IVIG likely exerts its therapeutic effect in autoimmune conditions through various mechanisms:
      • Direct neutralization of autoantibodies and cytokines
      • Altered function of effector mechanisms (FcR) - favoring anti-inflammatory responses
      • Accelerated elimination of pathogenic antibodies

    FcRn Inhibitors

    • Specific FcRn inhibitors can impact the pharmacokinetics of tracer antibodies at significantly lower doses than IVIG (15-60 mg/kg vs. 1-3 g/kg).
    • This was first demonstrated in 2005, highlighting the potential of specific FcRn inhibitors.

    EFGARTIGIMOD (VYVGART) – First FcRn Inhibitor

    • This first-in-human study demonstrated sustained reduction in circulating IgG concentrations in healthy individuals.
    • The maximum effect observed was around 75-85% reduction in IgG.
    • This trial did not show an increased risk of infections.

    Chimeric Autoantibody Receptor T-Cells (CAAR-T)

    • This innovative therapy is analogous to CAR-T therapy for cancer.
    • T cells are engineered to target and eliminate autoreactive B cells.
    • Unlike CAR, CAAR-T uses an autoantigen for activation, where autoantibodies and BCRs recognizing the antigen bind to the CAAR-T, inducing activation.
    • This approach offers greater specificity than other therapies.
    • CAAR-T has the potential to be curative, though further research is needed.

    Hypersensitivity Reactions

    • Hypersensitivity reactions are harmful immune responses to foreign antigens, including environmental antigens, drugs, and microbes.
    • These reactions can be specific to different types of antigens, including self-antigens (autoimmunity) and nonmicrobial antigens (allergic diseases).
    • Healthy individuals typically do not react to common harmless environmental substances, however, a significant portion of the population is abnormally responsive to certain substances.
    • These individuals produce IgE antibodies that cause allergic diseases.

    Classification of Hypersensitivity Diseases

    • Hypersensitivity diseases are classified based on the immune response and effector mechanism responsible for cell and tissue damage.
    • These mechanisms involve antibodies (types I, II and III) and T cells (type IV).
    • Allergic diseases are unique in their involvement of type I hypersensitivity reactions mediated by IgE.

    Autoimmunity

    • Autoimmunity is a failure of the body's self-tolerance mechanisms, leading to an immune response against self-antigens.
    • This can occur due to a lack of normal self-tolerance development, or when microbes are unusually resistant to eradication, resulting in persistent infection.
    • Autoantibodies can be either receptor agonists or antagonists, affecting the activity of target receptors:
      • Agonist autoantibodies: Mimic natural ligands and activate receptors in the absence of the actual ligand, causing overproduction (e.g., Graves' disease).
      • Antagonist autoantibodies: Block receptors and prevent their activation by natural ligands, leading to reduced function (e.g., myasthenia gravis).
    • Autoantibodies can also target cell surface receptors, causing disease by mimicking the natural ligand (agonist) or by blocking the natural ligand (antagonist).

    Antibody-mediated Diseases

    • These diseases can be caused by autoantibodies or antibodies specific for microbes.
    • Three main mechanisms destroy red blood cells (RBCs) in autoimmune hemolytic anemia:
      • Phagocytosis by macrophages that bear Fcγ receptor, complement receptor, or both.
      • Complement-mediated lysis of opsonized erythrocytes.
    • Antibody-mediated glomerulonephritis often results from deposition of immune complexes, as seen in Goodpasture’s syndrome and systemic lupus erythematosus (SLE).

    Immune Complex-mediated Diseases (ICMD)

    • ICMD is primarily caused by inflammation within blood vessel walls due to complement activation and leukocyte Fc receptor binding to antibodies in deposited immune complexes.
    • These complexes usually form in the circulation and deposit in various tissues, causing systemic disorders.
    • The complexes can involve antibodies bound to self-antigens or foreign antigens.

    T cell-mediated Diseases

    • T cells can injure tissues by producing cytokines that induce inflammation or by directly killing target cells.
    • CD4+ T cells of the Th1 and Th17 subsets mainly elicit inflammatory reactions.
    • CD8+ CTLs are primarily responsible for cell killing in some T cell-mediated disorders.
    • The T cells triggering tissue injury can be autoreactive or specific for foreign protein antigens.
    • Delayed-type hypersensitivity (DTH) reactions are often triggered by microbial infection, contact sensitization with chemicals or environmental antigens, or protein antigen injections.

    Type 4 Hypersensitivity Reaction

    • The Mantoux Test (Purified Protein Derivative, PPD, or Tuberculin Skin Test) is a type 4 hypersensitivity reaction used to detect prior exposure to Mycobacterium tuberculosis.
    • A positive result indicates that the individual has been exposed to M.tuberculosis and has developed a DTH reaction to the PPD antigen.

    Therapeutic Approaches to Immunologic Diseases

    • These approaches aim to reduce immune activation and the harmful consequences of autoimmune reactions.
    • Examples include cytokine antagonists, immunosuppressants, monoclonal antibodies, and therapies targeting specific pathways of immune response.

    Systemic Lupus Erythematosus (SLE)

    • This autoimmune disease is characterized by an overactive immune system that produces autoantibodies targeting various self-antigens.
    • These autoantibodies can deposit in tissues as immune complexes, leading to inflammation and organ damage.

    Rheumatoid Arthritis (RA)

    • RA is an autoimmune disease characterized by inflammation and joint damage, often caused by autoantibodies targeting components of synovial fluid.
    • A significant proportion of RA patients produce rheumatoid factor, a type of autoantibody targeting the Fc region of human IgG.
    • Therapy often involves targeting TNF-α to reduce inflammation and progression of symptoms.

    Other Key Points

    • Anti-TNF-α treatments can be effective in managing autoimmune diseases by reducing inflammation and tissue damage caused by the immune system.

    Graft Arteriosclerosis

    • Arterial lesions in graft arteriosclerosis cause a decrease in blood flow to the graft
    • Eventually, the graft parenchyma is replaced by fibrous tissue

    Interleukin-2 (IL-2) Function

    • IL-2 is a cytokine that stimulates the growth and survival of T lymphocytes
    • It plays a role in both the development of effector T cells and memory T cells
    • IL-2 also promotes the survival and function of regulatory T cells, which help to control immune responses

    Immune Synapse

    • An immune synapse is formed between an antigen-specificT cell and an antigen-presenting cell (APC)
    • The synapse is where signaling machinery of the T cell is assembled to regulate T cell activation
    • The synapse serves as an interface for TCR triggering, facilitating sustained and effective T cell signaling
    • Secretory granule contents and cytokines are delivered from the T cell to the APC through the synapse
    • The synapse can degrade signaling molecules, contributing to the termination of T cell activation.

    Immunosuppressive Drugs

    • Immunosuppressive drugs are used to suppress the immune system, preventing organ rejection in transplant recipients
    • Drugs achieve this by targeting various aspects of the immune system, including cell signaling pathways and inflammatory responses

    Corticosteroids

    • Corticosteroids are immunosuppressive drugs that affect gene expression
    • Corticosteroids bind to glucocorticoid receptors (GRs) in the cytoplasm, which then translocate to the nucleus
    • In the nucleus, GRs bind to glucocorticoid response elements (GREs) and interact with other coactivators
    • This leads to the activation of anti-inflammatory genes, such as secretory leukoprotease inhibitor (SLPI), mitogen-activated protein kinase phosphatase (MKP)-1, inhibitor of nuclear factor-κB (IκB-α), and glucocorticoid-induced leucine zipper protein (GILZ).
    • Corticosteroids also suppress inflammatory genes activated by inflammatory stimuli like interleukin (IL)-1β or tumour necrosis factor (TNF)-α
    • By inhibiting coactivator activity and recruiting histone deacetylase (HDAC)2, corticosteroids lead to suppression of inflammatory gene expression

    Transplant Rejection

    • The failure of skin grafting is due to an inflammatory reaction called rejection
    • Graft rejection originates from an adaptive immune response, exhibiting memory and specificity
    • Transplantation of cells/tissues between genetically nonidentical individuals leads to rejection due to an adaptive immune response
    • Grafts between genetically identical individuals (identical twins) are not rejected.
    • Grafts between genetically nonidentical individuals (different inbred strains) are almost always rejected.
    • Offspring from a mating between two different inbred strains will not reject grafts from either parent.

    Molecular Basis of Direct Recognition of Allogeneic MHC Molecules

    • MHC molecules present peptides on the cell surface, contributing to the structure recognized by alloreactive T cells
    • These peptides may be derived from proteins present in both donor and recipient, but are displayed by allogeneic MHC molecules on the graft cells
    • This results in a different complex from the self peptide–self MHC complexes
    • Alloreactive T cells may be activated by the polymorphic amino acid residues of the allogeneic MHC molecule alone.

    Activation of Alloreactive T cells

    • T cell responses to organ grafts can be initiated in the lymph nodes draining the graft
    • Grafted organs contain APCs like DCs, which express donor MHC molecules
    • These donor APCs migrate to lymph nodes and present unprocessed allogeneic MHC molecules to the recipient's T cells
    • This is known as direct MHC allorecognition.
    • Host DCs can migrate into the graft, acquire graft alloantigens, and present them in the draining lymph nodes, this is known as the indirect pathway.

    Hyperacute Rejection

    • Hyperacute rejection happens immediately after transplantation
    • It is caused by pre-existing antibodies in the host circulation that attack donor endothelial antigens
    • This leads to thrombotic occlusion of the graft vasculature, often within minutes to hours

    Acute Cellular Rejection

    • Acute cellular rejection occurs more slowly than hyperacute rejection
    • It is characterized by CTL-mediated killing of graft parenchymal cells and endothelial cells
    • It also involves inflammation caused by cytokines produced by helper T cells

    Acute Antibody-Mediated Rejection

    • Alloantibodies cause acute rejection by binding to alloantigens, mainly HLA molecules, on vascular endothelial cells
    • This leads to endothelial injury, intravascular thrombosis, and subsequent graft destruction.
    • Activation of complement pathway by these antibodies results in cell lysis, neutrophil recruitment, and thrombus formation.
    • Antibodies can also engage Fc receptors on neutrophils and NK cells, promoting endothelial cell death.
    • Antibody binding to endothelial cells may trigger intracellular signaling, increasing inflammatory and procoagulant molecule expression.

    Chronic Rejection

    • Arterial occlusion due to intimal smooth muscle cell proliferation is a common chronic rejection lesion
    • This eventually leads to graft failure due to ischemic damage
    • Arterial changes are called graft vasculopathy or accelerated graft arteriosclerosis
    • It commonly occurs in cardiac and renal allografts, developing within 6 months to a year after transplantation.
    • Activation of alloreactive T cells and secretion of IFN-γ and other cytokines contribute to vascular smooth muscle cell proliferation.

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    Related Documents

    Complement System PDF
    Immunogenicity: A Comprehensive Overview PDF
    Immune System: Skin and Mucosal Surfaces PDF
    E3 4 PDF - Central and peripheral tolerance to self antigens
    Autoimmune Disorders PDF
    Hypersensitivity Reaction Classification PDF
    E3 7 Transplant Rejection PDF

    Description

    Explore the mechanisms of complement activation and its regulation in this quiz. Understand how factors like DAF and Factor H prevent damage to host cells while enabling an immune response. Learn about the functions and deficiencies of the complement system, including its role in conditions like Paroxysmal Nocturnal Hemoglobinuria.

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