Podcast
Questions and Answers
What is the primary role of antibodies in humoral immunity?
Where are antibodies primarily produced in the body?
How do antibodies neutralize the infectivity of microbes?
What mediates the effector functions of antibodies?
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What is one mechanism by which opsonized particles are phagocytosed?
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What is a consequence of insufficient regulation of complement activation?
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Which step is targeted by regulatory mechanisms to control complement activation?
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What is a characteristic feature of Paroxysmal nocturnal hemoglobulinuria (PNH)?
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How does the absence of CD59 contribute to PNH symptoms?
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What is a common treatment for the iron loss associated with PNH?
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What condition is caused by a deficiency of C1 INH?
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What is the role of eculizumab in treating PNH?
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What characterizes the clinical episodes of hereditary angioedema (HANE)?
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Which treatment is commonly used for hereditary angioedema?
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In cases of acquired C1 inhibitor deficiency, what treatment is effective?
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Which deficiency is associated with the highest risk of neisserial infections?
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What is the role of meningococcal vaccination in complement deficiencies?
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Which complement deficiency is associated with recurrent respiratory infections?
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What triggers the classical pathway of complement activation?
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Which component is implicated in the life-threatening condition of meningitis due to complement deficiencies?
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How do the major pathways of the complement system converge?
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What pathway of complement activation is initiated by circulating lectins binding to carbohydrates on pathogens?
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What does immunogenicity refer to in relation to therapeutic proteins?
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What is a common consequence of the formation of Anti-Drug Antibodies (ADA)?
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Which factor makes predicting and mitigating immunogenicity particularly challenging?
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How is immunogenicity information typically presented in the labels of biotherapeutics?
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Which mechanism is NOT associated with the effects of immunogenicity on safety and efficacy?
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What is primarily reduced by the co-exposure of FVIII and phosphatidylserine?
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What is a necessary condition for robust tolerance induction in the co-delivery of antigen and drug?
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What effect does rapamycin have in the context of immune response?
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What is a noted consequence of the increased generation of regulatory T cells?
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What effect does decreased dendritic cell activation have on the immune system?
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What is the dosage range of low dose methotrexate used as an anti-inflammatory agent in rheumatoid arthritis?
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Which of the following agents is NOT mentioned as reducing ADA development against adalimumab?
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What effect does low dose methotrexate have when used with adalimumab?
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How do T cell epitopes influence immunogenicity?
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What is the primary purpose of in silico tools in the context of immunogenicity?
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What is a downside of long-term treatment with immunosuppressive agents?
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Which of the following statements about methotrexate is true?
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Which class of drugs has been shown to also reduce ADA development besides methotrexate?
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What is the relationship between T cell epitopes and immunogenicity risk?
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What is a common reason for combining antirheumatic drugs like methotrexate with biologics like adalimumab?
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What is the role of the skin and mucosal surfaces in the immune system?
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Which best describes the function of M cells in the gastrointestinal immune system?
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What distinguishes primary lymphoid organs from secondary lymphoid organs?
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Which component of the gastrointestinal innate immune system acts as a physical barrier?
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How are the gut-homing properties of intestinal lymphocytes developed?
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What type of cells in the intestinal mucosa are responsible for the differentiation of Th17 effector T cells?
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Which cytokine is involved in promoting the differentiation of regulatory T cells in the intestine?
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What is a key function of keratinocytes in the epidermis?
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Which of the following molecules is involved in directing effector T cells to the skin?
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What stimulates the production of vitamin D, which is involved in skin-homing properties of effector lymphocytes?
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What type of immune cells primarily take up and process protein antigens from microbes in the gastrointestinal tract?
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Which cytokine is NOT mentioned as being involved in the differentiation of Th17 effector T cells?
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What induces the expression of the chemokine receptor CCR9 on naive B or T cells in GALT?
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What type of interactions occurs between helper T cells and IgM+ B cells during T-dependent IgA class switching?
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What process allows IgA to be transported from the basolateral to the luminal side of epithelial cells?
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What role do dendritic cells play in the gastrointestinal immune system?
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Which mechanism is NOT involved in IgA class switching?
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Where do plasma cells primarily produce IgA in the body?
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What type of antigens do dendritic cells in Peyer’s patches capture to activate naive CD4+ T cells?
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What is the role of the poly-Ig receptor in the transport of IgA?
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What occurs during central tolerance when immature lymphocytes recognize self antigens?
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What is the role of the AIRE protein in T cell tolerance?
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Which mechanism is NOT a part of peripheral tolerance?
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What is the primary consequence of negative selection in the thymus?
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Which type of lymphocyte specifically develops into regulatory T cells during central tolerance?
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What occurs when T cells recognize self antigens without costimulation?
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Which statement correctly describes the role of CTLA-4 in T cell activation?
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Which cytokine is primarily produced by regulatory T cells to suppress immune responses?
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What mechanism does CTLA-4 utilize to inhibit T cell activation?
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How does TGF-β1 contribute to immune modulation?
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What effect do anergic T cells exhibit in response to antigen stimulation?
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What is a key function of regulatory T cells in immune responses?
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Which protein is targeted for degradation when TCR signaling is inhibited in anergic T cells?
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What is the primary function of Interleukin-10 (IL-10) in the immune response?
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Which statement accurately describes tolerogenic antigens?
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What happens to immature B lymphocytes that recognize self antigens with high affinity?
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What is central tolerance in the context of B cells?
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Which condition is likely to result from the failure of self-tolerance in the immune system?
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How does IL-10 affect T cell activation?
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What type of immune tolerance is characterized by recognizing self antigens in peripheral tissues?
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What is one major way B cells contribute to autoimmune conditions?
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Which mechanism does Rituximab use to reduce B cell populations?
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What is a consequence of using B cell depleting monoclonal antibodies in autoimmune therapy?
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Which type of diseases have B cell depleting antibodies primarily been developed to treat?
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What distinguishes the use of B cell depleting antibodies in both autoimmune conditions and malignancies?
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What is a significant effect of anti-TNF treatment in patients with rheumatoid arthritis?
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Which of the following is a key advantage of kinase inhibitors compared to biologic treatments?
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What is a common side effect associated with approved kinase inhibitors?
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What is the role of cytokine blockade in treating autoimmune conditions?
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Which statement is true regarding the efficacy of TNF blockers?
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What is the primary use of intravenous immunoglobulin (IVIG)?
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At what high dose range is IVIG typically used to treat autoimmune conditions?
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What is a key mechanism by which IVIG acts in autoimmune conditions?
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What is a significant downside of using IVIG?
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Which of the following is NOT a mechanism through which IVIG is thought to work?
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Which condition was IVIG initially developed to treat?
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What effect does IVIG have on effector mechanisms?
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Why are the costs of IVIG treatments considered high?
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What is the impact of IVIG on pathogenic antibodies?
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Which of the following is a consequence of the plasma-derived nature of IVIG?
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What type of hypersensitivity reaction is unique to allergic diseases?
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What is the effect of autoantibodies that act as receptor agonists?
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What autoimmune condition is caused by autoantibodies against the TSH receptor?
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What occurs when autoantibodies act as receptor antagonists?
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What describes the mechanism by which antibodies against streptococcal antigens can cause rheumatic fever?
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Which type of hypersensitivity reaction is associated with autoimmune diseases?
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What is the primary immune response involved in allergic diseases?
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Which mechanism is primarily depended on T cells in hypersensitivity reactions?
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Which of the following statements about hypersensitivity responses is accurate?
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Which characteristic is typical of individuals with sensitivities to environmental antigens?
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What is the primary consequence of autoantibodies binding to acetylcholine receptors in myasthenia gravis?
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In Graves' disease, thyroid hormone production disregards the body's needs and the role of which hormone?
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What role does complement fixation play in autoimmune hemolytic anemia?
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Which mechanism primarily leads to muscle weakness in myasthenia gravis?
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How do autoantibodies differ from antibodies produced in response to infections?
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What is a potential outcome when antibodies act as antagonists at cell surface receptors?
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In the context of autoimmune diseases, what is a common characteristic of antibodies that cause tissue-specific damage?
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What immune response mechanism is involved in the phagocytosis of opsonized red blood cells in autoimmune hemolytic anemia?
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What effect does the presence of autoantibodies in Graves' disease have on the regulation of thyroid function?
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Which mechanism is NOT involved in the destruction of red blood cells in autoimmune hemolytic anemia?
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What effect does Interleukin-2 (IL-2) NOT have on T lymphocytes?
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What is the primary function of the immune synapse?
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What is a key consequence of the degradation of signaling proteins in the immune synapse?
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Which mechanism is associated with corticosteroids in the immune response?
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What does the immune synapse ensure during T cell signaling?
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What is the role of glucocorticoid receptors (GRs) after being activated by corticosteroids?
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Which process leads to the suppression of activated inflammatory genes by corticosteroids?
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What is the effect of histone acetyltransferases (HATs) on gene expression?
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How do corticosteroids primarily affect the expression of inflammatory genes?
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What is the significance of acetylation of core histone H4 in inflammatory gene expression?
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What is the primary mechanism behind the rejection of transplanted organs?
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Which situation would most likely lead to successful organ transplantation?
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What typically happens to skin grafts from unrelated donors in burn patients?
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What experimental observation first highlighted the issue of graft rejection?
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Which rule of transplantation immunology states that an (A × B) F1 animal will not reject grafts from either parent?
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What is a notable exception to the general rules of graft rejection?
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Which factor does NOT influence whether a graft will be rejected?
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Which statement best describes the outcomes when transplanting organs from different inbred strains?
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What should be expected when grafts derived from offspring are transplanted into one of the parents?
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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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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.
