Immunoglobulin Deficiencies and Autoimmune Disorders

Immunoglobulin Deficiencies

• Selective IgA Deficiency: Most common, low serum and mucosal IgA.
  • Increased risk of mucosal infections, especially viral, but many remain asymptomatic.
• Hyper-IgM Syndrome: Elevated IgM, due to mutations in CD40L or CD40 receptor, impacting B-cell activation and class switching.
  • Results in low IgA, IgG, and IgE, leading to recurrent pyogenic infections at mucosal sites due to ineffective opsonization.
• Wiskott-Aldrich Syndrome: Characterized by thrombocytopenia, eczema, and recurrent infections (both humoral and cellular immunity issues).
  • Caused by mutation in WASP gene, an X-linked condition. Bleeding is a major cause of death.
• Complement Deficiencies:
  • C5-C9 deficiencies: Increased risk of Neisseria infections (gonorrhea and meningitis).
  • C1 inhibitor deficiency: Leads to hereditary angioedema with edema in the skin, especially around the eyes, and mucosal surfaces.

Autoimmune Disorders

• General Principles:
  • Characterized by immune-mediated destruction of self tissues.
  • US prevalence is 1-2%.
  • Loss of self-tolerance: Self-reactive lymphocytes normally undergo central (thymus and bone marrow) or peripheral tolerance mechanisms.
    • Central Tolerance (thymus): Apoptosis or generation of regulatory T cells. AIRE mutations cause autoimmune polyendocrine syndrome.
    • Central Tolerance (bone marrow): Receptor editing or B-cell apoptosis.
    • Peripheral Tolerance: Anergy or apoptosis of T and B cells. Fas apoptosis pathway mutations lead to autoimmune lymphoproliferative syndrome (ALPS).
    • Regulatory T cells: Suppress autoimmunity by blocking T-cell activation and producing anti-inflammatory cytokines (IL-10 and TGF-β). CD25 polymorphisms linked to autoimmunity (multiple sclerosis and type 1 diabetes), FOXP3 mutations lead to IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked).
  • More common in women, especially childbearing age. Estrogen may reduce apoptosis of self-reactive B cells.
  • Likely caused by environmental triggers in genetically susceptible individuals.
    • Increased incidence in twins.
    • Association with certain HLA types (e.g., HLA-B27) and PTPN22 polymorphisms.
    • Environmental triggers may lead to bystander activation or molecular mimicry.
  • Clinically progressive with relapses and remissions, often with overlapping features. Explained by epitope spreading.

Systemic Lupus Erythematosus (SLE)

• Chronic, systemic autoimmune disease with frequent flares and remissions.
• Most common in middle-aged women, particularly African American and Hispanic women, but can occur in children and older adults (less gender bias).
• Antigen-antibody complexes damage multiple tissues (type III hypersensitivity reaction).
  • Poorly cleared apoptotic debris (e.g., from UV damage) activates self-reactive lymphocytes, leading to antibody production against host nuclear antigens.
  • Antigen-antibody complexes are initially low level and taken up by dendritic cells.
  • DNA antigens activate TLRs, amplifying the immune response (IFN-α).
  • Antigen-antibody complexes are subsequently generated at higher levels and deposit in various tissues, causing disease.
  • Deficiency of early complement proteins (C1q, C4, and C2) associated with SLE.
• Almost any tissue can be affected. Classic findings include:
  • Fever, weight loss, fatigue, lymphadenopathy, and Raynaud phenomenon.
  • 'Butterfly' rash across the face or discoid rash, especially after sun exposure.
  • Oral or nasopharyngeal ulcers (usually painless).
  • Arthritis affecting at least two joints.
  • Serositis (pleuritis and pericarditis).
  • Psychosis or seizures.
  • Renal damage.

Immunoglobulin Deficiencies

• Selective IgA Deficiency: Most common immunoglobulin deficiency, with low serum and mucosal IgA.
• Increased Risk of Mucosal Infections: Patients with IgA deficiency are at higher risk for viral infections in the mucosal lining. Most patients are asymptomatic.
• Hyper-IgM Syndrome: High IgM levels due to mutations in CD40L (on helper T cells) or CD40 receptor (on B cells).
• Inability to Deliver Second Signal: Mutations prevent the delivery of the second signal to helper T cells during B-cell activation, halting immunoglobulin class switching.
• Low IgG, IgA, and IgE: Deficiency in these immunoglobulins leads to frequent pyogenic infections, particularly at mucosal sites.
• Wiskott-Aldrich Syndrome: Characterized by thrombocytopenia, eczema, and recurrent infections, affecting both humoral and cellular immunity.
• Bleeding: A major cause of death in individuals with Wiskott-Aldrich Syndrome.
• Mutation in WASP Gene: X-linked genetic disorder caused by mutations in the WASP gene.
• Complement Deficiencies: Deficiencies in complement proteins can increase susceptibility to infections.
• C5-C9 Deficiencies: Increased risk for Neisseria infections, including N gonorrhoeae and N meningitidis.
• C1 Inhibitor Deficiency: Leads to hereditary angioedema, characterized by skin and mucosal swelling.

Autoimmune Disorders

• Immune-mediated Damage of Self Tissues: Autoimmune disorders result in the body's immune system attacking its own tissues.
• Loss of Self-Tolerance: Breakdown in the immune system's ability to distinguish self from non-self, leading to the activation of self-reactive lymphocytes.
• Central Tolerance: Established in the thymus and bone marrow, eliminating or regulating self-reactive lymphocytes.
  • AIRE Mutations: Result in autoimmune polyendocrine syndrome, a condition affecting multiple endocrine glands.
• Peripheral Tolerance: Mechanisms that suppress self-reactive lymphocytes that escape central tolerance.
  • Fas Apoptosis Pathway Mutations: Associated with autoimmune lymphoproliferative syndrome (ALPS).
• Regulatory T Cells: Suppress autoimmunity by blocking T-cell activation and producing anti-inflammatory cytokines.
  • CD25 Polymorphisms: Linked to autoimmune diseases like multiple sclerosis (MS) and type 1 diabetes mellitus (T1DM).
  • FOXP3 Mutations: Cause IPEX syndrome, an X-linked disorder characterized by immune dysregulation, polyendocrinopathy, and enteropathy.
• Women More Susceptible: Autoimmune disorders are more prevalent in women, particularly those of childbearing age.
• Estrogen's Role: Estrogen may play a role by reducing apoptosis of self-reactive B cells.
• Environmental Triggers in Genetically Susceptible Individuals: Often contribute to the development of autoimmune disorders.
  • Twin Studies: Higher incidence of autoimmune disorders in twins suggests a genetic component.
  • HLA Types and PTPN22 Polymorphisms: Associations with certain HLA types and PTPN22 genetic variations have been observed in individuals with autoimmune disorders.
  • Bystander Activation and Molecular Mimicry: Environmental triggers can lead to immune system activation against self-antigens.
• Clinical Progression: Autoimmune disorders have a fluctuating course with periods of flares and remissions and often exhibit overlapping features.
  • Epitope Spreading: The autoimmune response can expand to target additional self-antigens, contributing to the development of autoimmune disorders.

Systemic Lupus Erythematosus (SLE)

• Chronic Systemic Autoimmune Disease: SLE involves multiple organs and systems with intermittent periods of flares and remissions.
• Middle-aged Females Predisposed: SLE predominately affects middle-aged women, especially those of African American and Hispanic descent.
• Antigen-antibody Complex Damage: Damage to various tissues is mediated by antigen-antibody complexes (type III hypersensitivity reaction).
  • Apoptotic Debris: Poorly cleared apoptotic debris, for instance, from UV damage, triggers the production of autoantibodies against nuclear antigens by self-reactive lymphocytes.
  • TLR Activation: DNA antigens engage Toll-like receptors (TLRs), amplifying the inflammatory response.
  • Complement Protein Deficiency: Low levels of C1q, C4, and C2 complement proteins are associated with SLE.
• Multiple Tissue Involvement: SLE can affect almost any tissue in the body.
  • Classic Symptoms: Fever, weight loss, fatigue, lymphadenopathy, and Raynaud's phenomenon.
  • Skin Manifestations: Malar "butterfly" rash, discoid rash, especially triggered by sunlight exposure.
  • Oral and Nasopharyngeal Ulcers: Usually painless.
  • Arthritis: Joint inflammation affecting two or more joints.
  • Serositis: Inflammation of the pleural and pericardial linings.
  • Neurological Complications: Psychosis, seizures.
  • Kidney Damage: Renal involvement is a major complication.

Immunodeficiency Disorders

• X-Linked Agammaglobulinemia (Bruton's Agammaglobulinemia): Absence of mature B cells leads to severely impaired antibody production, recurrent bacterial infections (especially encapsulated bacteria), and low serum immunoglobulin levels.
• Common Variable Immunodeficiency (CVID): Diverse genetic and environmental causes, leading to low levels of IgG, IgA, and IgM. Recurrent bacterial and viral infections, as well as chronic diarrhea and autoimmune disorders, are common.
• Selective IgA Deficiency: Most common immunoglobulin deficiency, featuring low serum and mucosal IgA levels. Predisposes individuals to viral infections, especially at mucosal surfaces, but many remain asymptomatic.
• Hyper-IgM Syndrome: Characterized by elevated IgM levels, caused by mutations in CD40L or CD40 receptor, which are essential for B-cell activation and class switching. This results in low IgA, IgG, and IgE, leading to recurrent infections at mucosal surfaces.
• Wiskott-Aldrich Syndrome: X-linked recessive disorder caused by mutations in the WASP gene, leading to thrombocytopenia, eczema, and recurrent infections due to impaired humoral and cellular immunity. Bleeding is a major concern.
• Complement Deficiencies: Deficiencies in C5-C9 increase susceptibility to infections caused by Neisseria species (N gonorrhoeae and N meningitidis). Cl inhibitor deficiency results in hereditary angioedema, characterized by edema of the skin and mucosal surfaces.

Autoimmune Disorders

• General Principles: These disorders involve an immune response directed against self-antigens, leading to tissue damage. They are more common in females, especially of childbearing age, and are likely triggered by environmental factors in genetically susceptible individuals.
• Loss of self-tolerance: normally self-reactive lymphocytes are eliminated or suppressed. Mutations in AIRE gene lead to autoimmune polyendocrine syndrome. Mutations in Fas apoptosis pathway result in autoimmune lymphoproliferative syndrome.
• Systemic Lupus Erythematosus (SLE): Chronic, systemic autoimmune disease characterized by the formation of antigen-antibody complexes that damage multiple tissues. Commonly affects middle-aged women, especially African Americans and Hispanics.
• Classic features: Butterfly rash, discoid rash, oral/nasopharyngeal ulcers, arthritis, serositis (pleuritis, pericarditis), psychosis, seizures, and renal damage.
• Pathogenesis: Apoptotic debris, especially from UV damage, activates self-reactive lymphocytes, triggering the production of antibodies against host nuclear antigens. These antibodies form antigen-antibody complexes, which deposit in various tissues causing inflammation.
• Genetic predisposition: Associations with specific MHC class II alleles (e.g., HLA-DR2 and HLA-DR3) and other genetic factors influence susceptibility.

Immunoglobulin Deficiencies

• IgA Deficiency: Most common immunoglobulin deficiency, marked by low serum and mucosal IgA.
  • Patients usually asymptomatic, but experience increased risk of mucosal infections, particularly viral.
• Hyper-IgM Syndrome: Characterized by elevated IgM levels.
  • Caused by mutated CD40L (on helper T cells) or CD40 receptor (on B cells).
  • This disrupts B-cell activation and class switching, resulting in low levels of IgA, IgG, and IgE.
  • Patients suffer from recurrent pyogenic infections due to poor opsonization, especially at mucosal sites.
• Wiskott-Aldrich Syndrome: Characterized by thrombocytopenia, eczema, and recurrent infections (defective humoral and cellular immunity).
  • Caused by a mutation in the WASP gene (X-linked).
  • Bleeding is a major cause of death.
• Complement Deficiencies:
  • C5-C9 deficiencies: Increased risk of Neisseria infections (N gonorrhoeae and N meningitidis).
  • C1 inhibitor deficiency: Results in hereditary angioedema, causing edema of the skin and mucosal surfaces.

Autoimmune Disorders

• General Principles:
  • Characterized by immune-mediated damage to self tissues.
  • Involves loss of self-tolerance, where self-reactive lymphocytes are normally eliminated or controlled.
  • Central tolerance mechanisms in the thymus (T-cell apoptosis or regulatory T cell generation) and bone marrow (receptor editing or B-cell apoptosis) are crucial.
  • Peripheral tolerance mechanisms like anergy and apoptosis of T and B cells are also important.
  • Regulatory T cells suppress autoimmunity by blocking T-cell activation and producing anti-inflammatory cytokines.
  • More common in women, especially those of childbearing age.
  • Likely involves environmental triggers in genetically susceptible individuals.
  • Characterized by clinical progression with relapses and remissions.
• Systemic Lupus Erythematosus (SLE):
  • Chronic, systemic autoimmune disease with flares and remissions.
  • Typically affects middle-aged women, particularly African American and Hispanic women.
  • Antigen-antibody complexes damage multiple tissues (type III hypersensitivity reaction).
  • Poorly cleared apoptotic debris can trigger self-reactive lymphocytes to produce antibodies against host nuclear antigens.
  • Deficiency of early complement proteins (C1q, C4, and C2) is associated with SLE.
  • Can involve almost any tissue, with classic findings:
    • Fever, weight loss, fatigue, lymphadenopathy, and Raynaud phenomenon.
    • Malar 'butterfly' rash or discoid rash, especially upon sun exposure.
    • Oral or nasopharyngeal ulcers (usually painless).
    • Arthritis (usually involving ≥ 2 joints).
    • Serositis (pleuritis and pericarditis).
    • Psychosis or seizures.
    • Renal damage.

Immunoglobulin Deficiency

• IgA deficiency is the most common immunoglobulin deficiency.
• Patients with IgA deficiency have low serum and mucosal IgA and are at increased risk for mucosal infection, especially viral, however, most are asymptomatic.
• Hyper-IgM syndrome is characterized by elevated IgM due to mutated CD40L or CD40 receptor.
• Patients with Hyper-IgM syndrome are at increased risk for recurrent pyogenic infections at mucosal sites due to poor opsonization.
• Wiskott-Aldrich syndrome is characterized by thrombocytopenia, eczema, and recurrent infections; it is X-linked.

Complement Deficiencies

• C5-C9 deficiencies increase risk for Neisseria infection.
• C1 inhibitor deficiency results in hereditary angioedema, which clinically manifests as edema of the skin and mucosal surfaces.

Autoimmune Disorders

• Autoimmune disorders are characterized by immune-mediated damage of self tissues and can involve loss of central or peripheral tolerance.
• Classic autoimmune disorder features include:
• More common in women, often affecting women of childbearing age.
• Estrogen may reduce apoptosis of self-reactive B cells.
• Environmental triggers may lead to bystander activation or molecular mimicry.
• Autoimmune disorders are clinically progressive with relapses and remissions.
• Autoimmune disorders often show overlapping features, which can be explained by epitope spreading.

Systemic Lupus Erythematosus (SLE)

• SLE is a chronic, systemic autoimmune disease that can be characterized by flares and remissions.
• The underlying cause of SLE is unclear, but it may be due to poorly cleared apoptotic debris, which activates self-reactive lymphocytes that then produce antibodies to host nuclear antigens.
• SLE is characterized by a variety of clinical symptoms, including:
• Fever
• Weight loss
• Fatigue
• Lymphadenopathy
• Raynaud phenomenon
• Malar 'butterfly' rash
• Discoid rash
• Oral or nasopharyngeal ulcers (usually painless)
• Arthritis (usually involving ≥ 2 joints)
• Serositis (pleuritis and pericarditis)
• Psychosis or seizures
• Renal damage

This quiz covers essential knowledge on various immunoglobulin deficiencies, including Selective IgA Deficiency, Hyper-IgM Syndrome, and Wiskott-Aldrich Syndrome. Additionally, it touches on complement deficiencies and their implications. Test your understanding of these conditions and their effects on the immune system.