Immunodeficiencies LO3

Lecture Outcome Number Three: Immunodeficiencies of Innate Immunity

Overview

  • Focus: Comparison and contrast of genes, clinical outcomes, and treatments of immunodeficiencies associated with innate immunity, specifically:

    • Complement deficiency

    • Leukocyte adhesion deficiency

  • Context: Components of the innate immune system are diverse, with various cells and proteins contributing to the immune response.

Components of the Innate Immune System

  • Key Cells:

    • Basophils

    • Eosinophils

    • Mast Cells

    • Important for Type II Immunity

    • Neutrophils

    • Important for Type III Immunity

    • Macrophages

    • Associated with Type I Immunity

    • Complement Proteins

  • Implications: Defects in any of these components can lead to various clinical outcomes.

Complement Deficiency

Definition of Complement

  • Description: A system of soluble recognition receptors and effector molecules found in serum.

  • Function: Detect and destroy pathogens.

  • Details:

    • Present in blood, constitutively expressed, and synthesized in the liver.

Activation of the Complement System

  • Process:

    1. Trigger in the complement pathway activates the cascade.

    2. Protease cascade amplification leads to the creation of C3 convertase.

    3. C3 convertase cleaves C3 into C3a and C3b.

  • Consequences of Activation:

    • Inflammation, leukocyte recruitment, phagocytosis and opsonization, formation of the membrane attack complex (MAC) which disrupts pathogen membranes.

Pathways of Complement Activation

  1. Classical Pathway:

    • Activated by antibodies binding to antigens (immune complexes).

  2. Mannose Binding Lectin (MBL) Pathway:

    • Soluble MBL binds to mannose residues on pathogen surfaces (absent on host cells).

  3. Alternative Pathway:

    • C3 spontaneously hydrolyzes and attaches to the pathogen surface.

  • Outcome of All Paths: All pathways lead to formation of C3 convertase, and result in the same downstream effects.

Clinical Outcomes of Complement Deficiency

  • Predicted Results: Deficiency expected to reduce immune response against extracellular microbes, leading to increased susceptibility to these pathogens.

  • Findings:

    • Defects in complement components are linked to susceptibility to:

    • Extracellular bacteria, particularly Neisseria species (e.g., Neisseria gonorrhoeae, Neisseria meningitidis).

    • Specific components C5 to C9 show increased susceptibility.

  • Treatment Strategies:

    • Antibiotics targeting Neisseria pathogens.

    • Vaccination against Neisseria meningitidis.

Unexpected Clinical Outcomes

  • Autoimmunity Links:

    • Defects in classical pathway components (C1, C2, C4) can lead to autoimmune conditions like Systemic Lupus Erythematosus (SLE).

  • Mechanism:

    • Defective components hinder clearance of immune complexes leading to their deposition in tissues, driven by type III hypersensitivity.

Leukocyte Adhesion Deficiency Type One

Definition

  • Overview: A defect in leukocyte migration leading to immobile leukocytes.

  • Characteristics of the Disorder:

    • Recurrent and severe bacterial infections, potentially fatal if untreated.

    • Typically caused by genuine rather than opportunistic pathogens.

    • Common manifestation includes severe gingivitis and delayed umbilical cord separation.

    • Patients exhibit high white blood cell counts, normal antibody responses, and delayed wound healing.

Treatment for Leukocyte Adhesion Deficiency

  • Prophylactic Antibiotics: Used to prevent infections.

  • Bone Marrow Transplantation: Discussed in relation to Severe Combined Immunodeficiency (SCID).

Mechanism of Leukocyte Adhesion

  • Inflammatory Response:

    • Inflammation triggers expression of adhesion molecules on vascular endothelium.

  • Types of Adhesion Molecules:

    1. Selectins: Facilitate rolling of leukocytes on endothelium under normal conditions.

    2. Integrins (Beta-Two Integrins):

    • Important for stable adhesion to vascular endothelium.

    • CD18: The beta chain of beta-two integrins is defective in LAD Type One.

Impact of Beta-Two Integrin Deficiency

  • Leukocyte Functionality:

    • White blood cells remain functionally normal but cannot migrate to sites of infection.

  • Consequences:

    • High numbers of white blood cells in circulation but ineffective due to inability to adhere and migrate.

Conclusion

  • Diverse Clinical Outcomes: Deficiencies in the complement and leukocyte adhesion pathways lead to varied clinical manifestations, from increased susceptibility to infections to autoimmunity. Understanding these mechanisms is vital for effective diagnosis and management of immunodeficiencies.