Disorders-of-the-Immune-System (2)

Disorders of the Immune System

The immune system plays a crucial role in defending the host against foreign organisms, effectively distinguishing between "self" and "non-self". Its primary functions involve not only safeguarding against microorganisms and toxins but also thwarting attacks from endogenous factors, including tumors, and facilitating tissue repair. This document provides an exploration into the normal physiology underlying the immune system and details the abnormalities leading to hypersensitivity diseases and immunodeficiency, providing comprehensive coverage of the immune response mechanisms.

Normal Structure of the Immune System

The immune system is composed of both antigen-specific and nonspecific components which work collaboratively yet function separately.

• Adaptive Immunity: This branch of the immune system is characterized by its specificity and ability to recall past encounters with antigens through antibody-mediated and cell-mediated responses. T and B lymphocytes are critical in recognizing specific antigens and generating immune memory.

• Innate Immunity: Serving as the first line of defense, innate immunity includes physical barriers such as epithelial tissues, along with various cellular defenders like phagocytes, dendritic cells, and complement proteins providing immediate protection against pathogens.

Cells of the Immune System

The immune system comprises various cellular players including:

• Monocytes and Macrophages: Monocytes mature into macrophages which are pivotal for processing antigens, secreting mediators for immune responses, and functioning as effector cells in tumor immunity.

• Lymphocytes: T cells (70–80% of lymphocytes) facilitate cellular immunity, whereas B cells (10–15%) are instrumental in humoral responses involving antibody production.

• Granulocytes: Including neutrophils, eosinophils, basophils, and mast cells. Neutrophils specialize in phagocytosis of foreign antigens, eosinophils combat parasites, and mast cells release mediators during allergic responses and immediate hypersensitivity.

Organs of the Immune System

Immune system organs are functionally divided into primary and secondary lymphoid organs:

• Primary Lymphoid Organs:

  • Bone Marrow: The origin of all immune cells.

  • Thymus: The site for T-lymphocyte development.

• Secondary Lymphoid Organs:

  • Lymph Nodes: Serve as filters for lymph, presenting antigens to immune cells.

  • Spleen: Filters blood and plays a crucial role in processing antigens.

  • GALT (Gut-associated lymphoid tissue): Involves immune responses in the gut.

Inflammatory Mediators and Cytokines

Inflammatory mediators orchestrate the immune response and can be categorized as follows:

• Preformed Mediators: Released from granules during activation, including histamine, proteoglycans, and proteolytic enzymes.

• Newly Generated Mediators: Include kinins, platelet-activating factors, and arachidonic acid metabolites (such as leukotrienes and prostaglandins), produced during immune responses.

• Cytokines: Soluble factors like interferons, interleukins, and tumor necrosis factor that modulate immune functions and regulate inflammation.

Innate and Adaptive Immunity

The immune response utilizes two levels of defense mechanisms:

• Innate Immunity:

  • Serves as the first line and is characterized by non-specific immediate responses via physical barriers, complement systems, and phagocytes.

  • Uses pattern recognition receptors (like TLRs) to identify pathogen signatures, triggering inflammatory processes.

• Adaptive Immunity:

  • Provides a specific and delayed response, creating immunological memory via B and T lymphocytes.

Antigens and Immune Response

Antigens, also known as immunogens, are external substances that elicit immune responses, demonstrating vast diversity in the human immune system's ability to respond to countless antigens.

• Antigen Processing: Specific immunogens necessitate capture and presentation by antigen-presenting cells (APCs) which display antigen fragments through MHC molecules.

• Antigen Recognition: T cells acknowledge processed antigens solely in association with MHC molecules, while B cells can bind to the native form of the antigen.

T-Lymphocyte Activation and Cellular Immunity

T lymphocytes centralize immune responses, essential for cellular immunity. They require antigen presentation facilitated by MHC molecules in addition to co-stimulatory signals for their activation.

• CD4+ Helper T Cells: Identify antigen through MHC class II, augment phagocytic activity, boost antibody production, and modulate inflammation.

• CD8+ Cytotoxic T Cells: Identify antigen presented with MHC class I, executing cell destruction in virus-infected cases, tumors, or foreign tissues.

• Regulatory T Cells: Essential for modulating immune responses and maintaining tolerance, they actively prevent autoimmunity via inhibitory cytokines and direct cellular interactions.

B-Lymphocyte Activation and Humoral Immunity

B lymphocytes are crucial for synthesizing antibodies, thus providing humoral immunity. Their activation mandates antigen binding to B-cell receptors alongside assistance from activated T cells.

1. Antigen Recognition: B cells recognize specific antigens via surface immunoglobulin receptors.

2. T Cell Help: Helper T cells afford cytokine support and CD40-CD40L engagement.

3. B Cell Proliferation: Activated B cells undergo clonal expansion for response.

4. Plasma Cell Differentiation: This leads to the transformation into antibody-secreting cells for effective immune response.

Antibody Structure and Function

Antibodies, or immunoglobulins, are specialized proteins binding to antigens. They share a common four-chain structure composed of two heavy and two light chains, featuring variable regions for specific antigen attachment and constant regions linked to effector functions.

• Antibody Classes:

  • IgG: Most prevalent in serum, exhibiting the longest half-life.

  • IgA: The primary immunoglobulin found on mucous membranes.

  • IgM: Predominates in early immune responses.

  • IgE: Involved in allergic reactions.

  • IgD: Their functions remain largely unclear.

• Functions of Antibodies: Include neutralizing toxins, opsonizing pathogens for phagocytosis, complement activation, and facilitating antibody-dependent cellular cytotoxicity.

Hypersensitivity Immune Responses

Hypersensitivity reactions occur when immune responses to antigens lead to tissue damage, classified into four types by Gell and Coombs for better understanding of their immunopathogenesis.

• Type I: Immediate IgE-mediated reactions responsible for allergic rhinitis, asthma, food allergies, and anaphylaxis, mediated by mast cell degranulation.

• Type II: Cytotoxic antibodies attach to surface antigens, activation of complement leading to cellular destruction (e.g., hemolytic anemia).

• Type III: Immune complex-mediated damage occurs when antigen-antibody complexes deposit in tissues, prompting inflammation (e.g., serum sickness).

• Type IV: Delayed T cell-mediated reactions create tissue damage via cytokine release, such as in contact dermatitis or tuberculin responses.

Allergic Rhinitis: Clinical Presentation

Allergic rhinitis arises from IgE-mediated hypersensitivity to environmental allergens, primarily affecting the upper respiratory mucosa. Its hallmark symptoms include nasal, ocular, and palatal pruritus, episodic sneezing, rhinorrhea, and nasal congestion.

• Common Symptoms:

  • Frequent sneezing

  • Itching of the nose and eyes

  • Clear nasal discharge (rhinorrhea)

  • Nasal congestion

• Physical Findings:

  • Pale or bluish nasal mucosa

  • Transverse nasal crease from habitual rubbing

  • Infraorbital cyanosis, termed "allergic shiners"

  • Serous otitis media.

Allergic Rhinitis: Pathogenesis

The pathogenesis of allergic rhinitis features a biphasic allergic reaction initiated by allergen cross-linking of IgE on mast cells and basophils, sparking a cascade of reactive mediators.

• Early-Phase Response: Occurs within minutes post-exposure, characterized by sneezing and rhinorrhea, driven by mediators like histamine, leukotrienes, and prostaglandins.

• Late-Phase Response: Arising 2-4 hours following exposure, this phase witnesses prolonged inflammation punctuated by eosinophil and T cell recruitment, producing persistent symptoms and leading to chronic inflammation and heightened tissue sensitivity.

Primary Immunodeficiency Diseases: Overview

Primary immunodeficiencies stem from genetic defects impairing immune development or functioning, resulting in greater vulnerability to infections, autoimmune conditions, and malignancies. Types include:

• Combined Immunodeficiency: Affects both B and T cells, causing severe infections by various pathogens (e.g., SCID).

• Humoral Immunodeficiency: Diminished antibody production leads to frequent sinopulmonary infections with encapsulated bacteria (e.g., XLA, CVID).

• Cellular Immunodeficiency: Involves compromised T-cell activities, enhancing susceptibility to various infections (e.g., DiGeorge syndrome).

• Phagocytic Disorders: Adverse affects on neutrophil operations, manifesting as recurrent skin infections and abscesses (e.g., Chronic Granulomatous Disease).

Severe Combined Immunodeficiency (SCID)

SCID denotes a group of disorders marked by severe deficits in both T and B lymphocytes, posing a life-threatening risk within 1-2 years without intervention.

• X-Linked SCID: Linked to a defective IL-2 receptor common gamma chain, obstructing multiple cytokine signals.

• ADA Deficiency: Resulting in the accumulation of toxic metabolites that lead to lymphocyte death.

• RAG Deficiency: Involves impaired VDJ recombination crucial for T and B cell receptor assembly.

• JAK3 Deficiency: Affects cytokine signaling vital for lymphocyte maturation.Children with SCID display failure to thrive, persistent diarrhea, and opportunistic infections. Bone marrow transplantation is the principal therapeutic approach.

Humoral Immunodeficiency Disorders

Humoral immunodeficiencies hinder antibody production and functionality, causing greater vulnerability to specific infections by encapsulated bacteria.

• X-Linked Agammaglobulinemia: BTK deficiency stops B-cell maturation.

• Common Variable Immunodeficiency: Diverse disorders associated with ineffective B-cell differentiation into antibody-secreting plasma cells.

• Selective IgA Deficiency: The most prevalent immunodeficiency affecting mucosal responses.Treatment via immunoglobulin replacement can restore humoral immunity, lessen infection susceptibility, and enhance patients' quality of life.

Phagocytic Cell Disorders

Disorders affecting phagocytes lead to inadequate microbial eradication, noted by recurrent infections at interfaces between the body and external environments, including skin infections and abscesses.

• Chronic Granulomatous Disease: Resulting from defective NADPH oxidase, impacting oxidative burst and bacterial eradication, particularly against catalase-positive organisms (e.g. Staphylococcus aureus).

• Leukocyte Adhesion Deficiency: Defective β2-integrin expression hampers leukocyte movement, leading to persistent infections and lack of pus formation.

• Hyper-IgE Syndrome: Defined by eczema, recurrent staphylococcal abscesses, and elevated IgE levels exceeding 3000 IU/mL.

AIDS: Clinical Overview

Acquired Immunodeficiency Syndrome (AIDS) results from Human Immunodeficiency Virus (HIV) infection, which progressively impairs CD4+ T lymphocyte levels, critical for maintaining cell-mediated immunity, increasing susceptibility to opportunistic infections and various malignancies.

• Acute HIV Infection: Characterized by a self-limited viral syndrome featuring fever, pharyngitis, lymphadenopathy, alongside elevated viral loads occurring 2-4 weeks post-infection.

• Clinical Latency: An asymptomatic period during which viral replication continues in lymphoid tissues, leading to a gradual decrease in CD4+ T cell numbers, lasting for several years without therapeutic intervention.

• AIDS: Defined by a CD4+ count below 200 cells/µL or the presence of AIDS-defining illnesses, including opportunistic infections and malignancies.

AIDS: Pathogenesis

HIV, a retrovirus, selectively targets CD4+ T lymphocytes, macrophages, and dendritic cells.

• Viral Entry: The virus's gp120 envelope protein binds to CD4 and chemokine co-receptors (CCR5 or CXCR4), facilitating viral entrance and replication.

• CD4+ T Cell Depletion: Results from direct viral cytopathic effects, sustained immune activation, and death of uninfected cells, progressively undermining immune responses.

1. Viral Entry: HIV gp120 binds with CD4 and co-receptors.

2. Reverse Transcription: Viral RNA transcribes into DNA via reverse transcriptase.

3. Integration: Viral DNA integrates into the host genome as provirus.

4. Viral Replication: Activated cells yield new virions infecting other host cells.

AIDS: Clinical Manifestations

AIDS presents a spectrum of clinical consequences, with declining CD4+ T-cell counts leading to weakened immune defences, marked by opportunistic infections, malignancies, and organ-specific issues.

• Respiratory Infections: Include Pneumocystis pneumonia, tuberculosis, and bacterial pneumonias, manifesting with fever, cough, and respiratory distress.

• Neurologic Complications: Features conditions like toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, and HIV-related dementia.

• Malignancies: Includes Kaposi sarcoma, non-Hodgkin lymphoma, and certain carcinomas related to impaired immune surveillance.

• Gastrointestinal Disease: Presents as oral/esophageal candidiasis, chronic diarrhea, and cachexia.Initiation of antiretroviral therapy can significantly hinder viral replication, rebuild immune functions, and remarkably boost life expectancy when started early.