Clinical Immunology: Hypersensitivity Reactions

Hypersensitivity

• Hypersensitivity (allergy): an amplified state of immune response to a harmless antigen, resulting in tissue injury, disease, or even death.
• Allergen: a type of antigen that can cause an allergic reaction.
• Hypersensitivity reactions are classified into four subtypes based on the mechanism (immune mediators) and the nature of the triggering antigen:
  • Type I: Immediate hypersensitivity, involving IgE-mediated degranulation of basophils or mast cells.
  • Type II: Antibody-mediated hypersensitivity, involving the interaction of antibodies with cell membrane or the extracellular matrix.
  • Type III: Immune complex-mediated hypersensitivity, involving the interaction of antibodies with soluble molecules to form immune complexes that deposit in tissues.
  • Type IV: Cell-mediated hypersensitivity, involving the direct attack of host cells by immune cells in the absence of antibody.

Type I Hypersensitivity

• Occurs within seconds to minutes of exposure to an antigen.
• Involves IgE-mediated degranulation of basophils or mast cells.
• Causes the release of vasoactive amines (e.g., histamine) and other inflammatory mediators.
• Examples: hay fever, asthma, food allergies, bee stings, and atopic dermatitis.

Type II Hypersensitivity

• Involves the interaction of antibodies with cell membrane or the extracellular matrix.
• Cell destruction is mediated by:
  • Complement-mediated cell lysis
  • Antibody-dependent cell-mediated cytotoxicity
  • Opsonization
• Examples: hemolytic anemia, transfusion reaction, and autoimmune diseases.

Type III Hypersensitivity

• Involves the interaction of antibodies with soluble molecules to form immune complexes that deposit in tissues.
• Examples: Arthus reaction, serum sickness, and autoimmune diseases.

Type IV Hypersensitivity

• Involves the direct attack of host cells by immune cells in the absence of antibody.
• Examples: contact dermatitis, delayed-type hypersensitivity, and autoimmune diseases.

Laboratory Diagnosis

• Type I hypersensitivity: skin testing, RAST, and IgE ImmunoCAP test.
• Type II and III hypersensitivity: complement activation by complement fixation test.
• Type IV hypersensitivity: application of the antigen to the surface of the skin or injected intradermally.

Immunodeficiency

• Primary immunodeficiency: genetic or developmental defects of the immune system, present at birth.
• Secondary immunodeficiency: loss of immune function due to exposure to various agents, such as infections, malignancies, or immunosuppressive drugs.
• Examples of primary immunodeficiency: X-linked agammaglobulinemia, DiGeorge syndrome, and severe combined immunodeficiency (SCID).
• Examples of secondary immunodeficiency: AIDS, chemotherapy, and radiation therapy.### Primary Immunodeficiencies (PIDs)
• Classified into nine categories based on clinical features, immunologic defects, and genetic abnormalities:
  • Category 1: Combined Immunodeficiencies
  • Category 2: Combined Immunodeficiencies with Associated or Syndromic Features
  • Category 3: Predominantly Antibody Deficiencies (most common, representing 50% of PIDs)
  • Category 4: Diseases of Immune Dysregulation
  • Category 5: Congenital Defects of Phagocyte Number, Function, or Both
  • Category 6: Defects in Innate Immunity
  • Category 7: Autoinflammatory Disorders
  • Category 8: Complement Deficiencies
  • Category 9: Phenocopies of Primary Immunodeficiencies

Laboratory Evaluation of Immune Dysfunction

• Three important stages:
  • Clinical diagnostics
  • Laboratory diagnostics
  • Genetic diagnostic
• Screening tests:
  • Used for initial evaluation of suspected immunodeficiency
  • Can be performed in any hospital laboratory
  • Include patient history, complete blood count (CBC), and white blood cell (WBC) differential
  • May reveal reduced lymphocyte count, thrombocytopenia, and small platelets

Secondary Immunodeficiencies

• Caused by external factors, such as:
  • Acquired hypogammaglobulinemia (e.g., corticosteroid or immunosuppressant drug use, nutritional disorders, infections, chemotherapy, malignancy, nephrotic syndrome, other metabolic diseases, and hazardous environmental conditions)
  • Agent-induced immunodeficiency (e.g., environmental agents, such as immunosuppressive drugs and accidental radiation exposure)
  • Extremes of age (e.g., young and elderly)
  • Severe malnutrition affecting both innate and adaptive immunity
  • Human immunodeficiency virus (HIV)

HIV Laboratory Testing

• Enzyme-linked immunosorbent assay (ELISA)
• Western blot
• Indirect fluorescent antibody (IFA)
• Polymerase Chain Reaction (PCR)

Treatment of Immune Deficiencies

• Depends on the causative agent
• Examples:
  • Enzyme replacement therapy
  • Gene therapy
  • Interferon
  • Hematopoietic stem cell transplant
  • Bone marrow transplantation
  • Protective isolation
  • Immunoglobulin replacement therapy
  • Prophylactic treatment for fungus and viruses

Autoimmunity

• Autoimmune diseases:
  • Conditions in which damage to organs or tissues results from the presence of autoantibody or autoreactive cells
  • Examples: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA)
• Mechanisms of self-tolerance:
  • Clonal deletion
  • Receptor editing
  • Clonal anergy
  • Peripheral tolerance
  • Regulatory T cells (Tregs)

Autoimmune Diseases

• Systemic lupus erythematosus (SLE):
  • Chronic systemic inflammatory disease
  • Alternating exacerbations and remissions
  • Peak age of onset: 20-40 years
  • Affects women more than men
  • More common in African Americans and Hispanics
  • Signs and symptoms: fatigue, weight loss, malaise, fever, anorexia, joint involvement, skin manifestations
  • Diagnosed with antinuclear antibodies (ANA) and anti-double-stranded DNA (anti-ds-DNA) antibodies
• Rheumatoid arthritis (RA):
  • Systemic autoimmune disorder
  • Characterized by symmetric, erosive arthritis of the peripheral joints
  • Can also affect multiple organs
  • Women are three times as likely to be affected as men
  • May occur at any age, but typically strikes between 35-50 years
  • Progress of the disease varies, with spontaneous remissions or active disease
  • Complications: heart attack, stroke, anemia, formation of subcutaneous nodules, pericarditis, lymphadenopathy, splenomegaly, interstitial lung disease, or vasculitis### Rheumatoid Arthritis (RA)
• IgM antibodies combine with IgG, forming immune complexes that deposit in joints, leading to a type III hypersensitivity reaction and activation of the classical complement cascade.
  • C3a and C5a are generated, acting as chemotactic factors for neutrophils and macrophages.
  • Chronic inflammation damages the synovium.
• Anti-citrullinated protein (anti-CCP) antibodies are a more specific marker for RA detection than RF.
• The earliest lesions in rheumatoid joints show:
  • Increased cells lining the synovium.
  • Infiltration of mononuclear cells, mostly CD4 T lymphocytes.
  • Scattered CD8 T cells, B cells, and antibody-producing plasma cells.
  • Macrophages and neutrophils attracting to the area, forming a pannus that grows into the joint space and invades the cartilage.

Diagnosis of Rheumatoid Arthritis (RA)

• Diagnosis is based on a combination of clinical manifestations, radiographic findings, and laboratory testing.
• RF is often tested for to aid in making the initial diagnosis, but a negative result does not rule out RA, and a positive result is not specific for RA.
• Anti-CCP EIA assays have better sensitivity and specificity, making it a more reliable indicator of RA.

Treatment of Rheumatoid Arthritis (RA)

• Traditional therapy includes anti-inflammatory drugs like salicylates and ibuprofen to control local swelling and pain.
• Disease-modifying antirheumatic drugs (DMARDs) like hydroxychloroquine and sulfasalazine are used.
• Biological agents that block the activity of TNF-α, such as infliximab and adalimumab, are used to halt joint damage.

Autoimmune Thyroid Diseases (AITDs)

• AITDs encompass conditions like Hashimoto's thyroiditis and Graves' disease.
• Both conditions have distinct symptoms but share some common antibodies that interfere with thyroid function.
• Antibodies present in AITDs include:
  • Antibodies to thyroglobulin.
  • Thyroid peroxidase.
  • TSH receptors.

Diagnosis of Autoimmune Thyroid Diseases (AITDs)

• Diagnosis is based on the presence of the above antibodies, tested by indirect immunofluorescent assays, passive agglutination, and EIA.

Type I Diabetes Mellitus

• Characterized by insufficient insulin production caused by selective destruction of beta cells in the pancreas.
• Diagnosis is typically made by hyperglycemia.
• Immunoassays for antibodies to:
  • Insulinoma antigen 2 (IA-2 or ICA 512).
  • IA-2β (phogrin).
  • Anti-insulin antibodies.
  • Antibodies to the enzyme GAD.
  • Islet cell antibodies (ICAs).

Multiple Sclerosis (MS)

• Characterized by the formation of lesions called plaques in the white matter of the brain and spinal cord, leading to progressive destruction of the myelin sheath of axons.
• A combination of genetic and environmental factors contributes to the development of MS.
• Patients with MS have a higher concentration of antibody to EBV than the control population.
• Other viruses implicated in MS include measles, herpes simplex, varicella, rubella, influenza C, human herpes virus-6, and some parainfluenza viruses.
• Diagnosis of MS is supported by:
  • Antibody production against a myelin basic protein peptide.
  • Magnetic resonance imaging (MRI).
• There is no single laboratory test that can confirm an MS diagnosis.