Chapter 15 Disorders of the Immune Response

An immunodeficiency is defined as an absolute or partial loss of the normal immune response that places a person at risk for the development of infection or malignancy.

Primary disorders are inherited, as the underlying genetic defect is present as birth

develop sometime later in life in response to another disease entity or condition.

a.Transient Hypogammaglobulinemia of Infancy:

•   Temporary low levels of antibodies in infants.
• Primary Humoral Immunodeficiency Disorders: Genetic defects affecting B cell function.
• X-Linked Agammaglobulinemia - Reduced levels of immunoglobulins (IgG, IgA, IgM), leading to increased susceptibility to infections. X-linked recessive.
• Common variable immunodeficiency- Heterogeneous group of disorders. Variable antibody levels, recurrent infections, and impaired B cell function. Usually in adolescence or adulthood onset.
• Selective deficiency of IgG, IgA, and IgM - Selective deficiencies in specific immunoglobulins (IgG, IgA, IgM), resulting in an increased risk of infections.
• Secondary Humoral Immunodeficiency Disorders: Acquired deficiencies in B cell function.
• Increased loss of immunoglobulin - Excessive loss of immunoglobulins through the kidneys due to nephrotic syndrome, leading to weakened immune function.
• Nephrotic Syndrome: A kidney disorder characterized by proteinuria, edema, hypoalbuminemia, and hyperlipidemia.

Congenital disorder. Absence or underdevelopment of the thymus, leading to T cell deficiency and immune system dysfunction. Associated Features: Cardiac abnormalities, Tetany due to hypocalcemia, and facial anomalies.Hyper-IgM Syndrome:Genetic disorder. Impaired class-switching of immunoglobulins, specifically IgM, leading to increased susceptibility to infections. Subtypes: Several genetic mutations associated with this syndrome.

Immune suppression due to malignant diseases like Hodgkin disease, leading to impaired T cell function.

• Mechanism: Cancer-related factors and treatments contribute to immunosuppression.
• Transient Suppression of T-Cell Production and Function due to Acute Viral Infection:

Temporary suppression of T cell production and function during acute viral infections, compromising the immune response.

• Recovery: T cell function typically returns after resolution of the viral infection.
• HIV-AIDS:
• Human Immunodeficiency Virus (HIV) infection leading to progressive T cell depletion, compromising the immune system.
• Stages: Acute infection, clinical latency, and acquired immunodeficiency syndrome (AIDS).

Congenital disorder. Absence or underdevelopment of the thymus, leading to T cell deficiency and immune system dysfunction. Associated Features: Cardiac abnormalities, Tetany due to hypocalcemia, and facial anomalies.

Genetic disorder. Impaired class-switching of immunoglobulins, specifically IgM, leading to increased susceptibility to infections. Subtypes: Several genetic mutations associated with this syndrome.

• a.Primary: genetic
• Severe combined immunodeficiency syndrome - Profound deficiency in both B and T cells, leading to severe immunodeficiency.

    Subtypes

üX-linked

• üAutosomal recessive (ADA deficiency, Jak3 deficiency)
• Wiskott-Aldrich syndrome - X-linked genetic disorder. Immune deficiency, eczema, and thrombocytopenia (low platelet count). Increased Susceptibility and a higher risk of autoimmune disorders.
• Ataxia–telangiectasia - Autosomal recessive genetic disorder. Progressive neurological dysfunction, immune deficiency, and telangiectasias (dilated blood vessels). Higher risk of developing cancer.
• Combined immunodeficiency syndrome - Genetic disorder. Combined deficiency in B and T cell function, resulting in immunodeficiency. Etiology: Various genetic mutations associated with this syndrome.

• Secondary
• Irradiation - Acquired disorder. Exposure to ionizing radiation leading to suppression of both B and T cell functions. Clinical Use: Radiation therapy for cancer treatment.

Immune suppression and cytotoxic drugs - Acquired disorder. Use of immunosuppressive and cytotoxic drugs, such as in organ transplantation or autoimmune disease treatment, leading to combined immunodeficiency.

• Hereditary Deficiency of Complement Proteins - Inherited deficiencies in various complement proteins, impacting the overall function of the complement system. Increased susceptibility to infections and autoimmune conditions.
• Hereditary Deficiency of C1 Inhibitor (Angioneurotic Edema) - Deficiency of C1 inhibitor leading to uncontrolled activation of the complement system and episodes of angioneurotic edema. Angioneurotic Edema: Recurrent episodes of swelling in various body parts.

Conditions or diseases that lead to excessive consumption of complement factors. Depletion of complement factors, affecting the immune response.

Chronic Granulomatous Disease (CGD) - Impaired ability of phagocytes to generate reactive oxygen species, leading to recurrent bacterial and fungal infections. Granulomas may form as a response to persistent infections.Chédiak-Higashi Syndrome - Defective lysosomal trafficking, resulting in phagocytic dysfunction, albinism, and neurological abnormalities. Increased susceptibility to bacterial infections.

Drug-Induced (Corticosteroid and Immunosuppressive Therapy)- Use of corticosteroids or immunosuppressive drugs can suppress the activity of phagocytes, increasing the risk of infections. Clinical Applications: Immunosuppressive therapy in autoimmune diseases or transplantation.Diabetes Mellitus - Metabolic disorder. Diabetes can impair phagocytic function, contributing to an increased susceptibility to infections. Elevated blood glucose levels may negatively impact immune cell function. (impaired phagocytosis, reduced t function, delayed wound healing, increased inflammation)

Stem cell transplantation encompasses various approaches, including hematopoietic stem cell transplantation (HSCT) using bone marrow or umbilical cord blood, gene therapy involving the introduction of therapeutic genes into cells, and the utilization of stem cells from umbilical cord blood for transplantation. These techniques hold promise for treating a range of genetic disorders, hematological malignancies, and other conditions.

Anaphylactic (Systemic) - Rapid, severe allergic reactions involving systemic release of mediators like histamine. It can range from skin rash to life-threatening anaphylaxis.Reactions Atopic (Local) Reactions - Allergic reactions mediated by IgE, affecting specific tissues or organs. Allergic rhinitis, asthma, eczema

. Complement-Activated Cell Destruction:

Activation of complement system leading to cell destruction.

• Hemolytic anemia, blood transfusion reactions.
• Antibody-Dependent Cell Cytotoxicity:

Antibodies target cells for destruction by immune cells.

• Blood transfusion reactions, some autoimmune diseases.
• Complement- and Antibody-Mediated Inflammation:

Inflammatory response triggered by complement activation and antibody binding.

• Rheumatoid arthritis, autoimmune disorders.
• Antibody-Mediated Cellular Dysfunction:

Antibodies interfere with normal cellular function.

Myasthenia gravis, Graves' disease.

Allergic Contact Dermatitis:

 Delayed hypersensitivity reaction involving T cells.

• Poison ivy, nickel allergy.
• Hypersensitivity Pneumonitis:

Inflammatory lung disease triggered by exposure to inhaled antigens.

Farmer's lung, bird fancier's lung.

• reaction to proteins in natural rubber latex.
• Can range from skin irritation to severe anaphylaxis.
• Common Triggers: Medical gloves (latex), balloons, rubber products.

Transplantation immunopathology involves various mechanisms leading to graft rejection, including hyperacute and acute rejection, chronic rejection, and graft vasculopathy.

Graft-Versus-Host Disease

Occurs in hematopoietic stem cell transplantation, where donor T cells attack recipient tissues, leading to acute and chronic manifestations affecting multiple organs.

Development of a pruritic, maculopapular rash that begins on the palms and soles and frequently extends over the entire body

• Mechanism: Central tolerance in the bone marrow eliminates self-reactive B cells during development.
• Peripheral Tolerance: Mature B cells encountering self-antigens in the periphery may undergo further tolerance mechanisms to prevent autoimmunity.

• Central Tolerance: Negative selection in the thymus eliminates self-reactive T cells during maturation.
• Peripheral Tolerance: Regulatory T cells (Tregs) play a crucial role in suppressing potentially harmful immune responses and maintaining self-tolerance.

Hereditary

• Genetic Predisposition: Certain genetic factors increase susceptibility to autoimmune diseases.
• Examples: Family history of autoimmune disorders may contribute to an individual's risk.

Environmental Factors 

• Triggers: Environmental factors, such as infections, toxins, and stress, can trigger autoimmune responses.
• Molecular Mimicry: Pathogens may share similarities with self-antigens, leading to immune cross-reactivity.
• Hygiene Hypothesis: Reduced early exposure to infections may contribute to autoimmune disease risk.

• Clinical Presentation: Symptoms vary widely but may include fatigue, joint pain, skin rashes, and organ dysfunction.
• Laboratory Tests: Autoantibodies, inflammatory markers, and imaging studies aid in diagnosis.
• Specialized Testing: Some diseases require specific tests, such as anti-nuclear antibody (ANA) testing for systemic lupus erythematosus.

• Immunosuppression: Corticosteroids and other immunosuppressive drugs help control inflammation.
• Disease-Modifying Anti-Rheumatic Drugs (DMARDs): Target specific pathways to modify the course of the disease.
• Biologic Therapies: Targeted therapies that modulate specific components of the immune system.
• Plasma Exchange: Removal of autoantibodies from the blood in severe cases.
• Symptomatic Treatment: Pain management, physical therapy, and supportive care.