Study Notes on Immunodeficiency

Immunodeficiency: The absence or failure of normal function of one or more elements of the immune system.

Congenital (Primary) Immunodeficiencies: Result from genetic abnormalities affecting components of the immune system. They are inherited defects classified based on the site of lesion in the developmental or differentiation pathway of the immune system.
Acquired (Secondary) Immunodeficiencies: Result from infections, nutritional deficiencies, or medical treatments causing inadequate function of the immune system.

Caused by genetic defects that create blocks in B cell or T cell maturation/function.
Classified by the defect’s location within the immune system development pathway.

B cell deficiencies:
- Histopathologic findings: Absent or reduced follicles and germinal centers in lymphoid organs, reduced serum immunoglobulin levels, potentially reduced T cell zones.
- Common infections: Pyogenic bacterial infections.
T cell deficiencies:
- Histopathologic findings: May show reduced T cell zones in lymphoid organs, decreased delayed-type hypersensitivity reactions, and defective T cell responses.
- Common infections: Viral infections and associated malignancies (e.g., Epstein-Barr virus associated lymphomas).
Innate immune deficiencies: Variable attributes depending on the defect.

Many congenital immunodeficiencies stem from genetic anomalies that block maturation in B and T lymphocytes.
Severe combined immunodeficiency (SCID) presents defects in both the B cell and T cell arms of the adaptive immune system.

X-linked agammaglobulinemia (Bruton’s agammaglobulinemia):
- Functional deficiencies: Decrease in all serum Ig isotypes and reduced B cell numbers.
- Mechanism of defect: Block in maturation beyond pre-B cells due to mutation in the B cell tyrosine kinase (Btk) gene located on X chromosome, leading to defective enzyme production.

DiGeorge syndrome:
- Functional deficiencies: Decreased T cells with normal or decreased B cells and serum Ig.
- Mechanism of defect: Abnormal development of the 3rd and 4th branchial pouches, causing thymic hypoplasia.

DiGeorge syndrome: Also known as congenital thymic aplasia/hypoplasia, associated with hypoparathyroidism and congenital heart disease resulting from abnormal fetal development.
Ataxia-telangiectasia: Characterized by motor coordination issues, variable T cell function, reduced IgG and IgA levels, high cancer incidence due to chromosome breakage affecting TCR and Ig genes.
Wiskott-Aldrich syndrome: Involves normal T cell numbers but progressive functional impairment; reduction in IgM with normal IgG, and elevated IgA and IgE levels; skin conditions like eczema are common.

Caused by defects in MHC class II transactivator (CIITA) protein gene, leading to a deficiency of class-II MHC molecules on antigen-presenting cells (APC), resulting in reduced CD4 T cell count and increased infection susceptibility.

Cyclic neutropenia: Characterized by low circulating neutrophils, leading to heightened infection risk due to regulation issues in neutrophil production.
Chronic granulomatous disease (CGD): Marked by lymphadenopathy and chronic lymph node issues due to NADPH oxidase defects affecting phagocytic respiratory bursts.
Leukocyte adhesion deficiency: Resulted from defects in CD11 or CD18 peptides causing impaired responses to chemotactic signals due to lack of complement receptor CR3.
Chediak-Higashi syndrome: Characterized by reduced intracellular killing, impaired chemotaxis, and phagosome-lysosome fusion complications.

Genetic deficiencies in different complement components lead to increased infection susceptibility; C3 deficiency is particularly severe.

Types: X-linked SCID and autosomal recessive SCID.
Functional deficiencies: Markedly decreased T cells, varying B cell levels, reduced serum immunoglobulin levels.
Mechanisms:
- X-linked SCID: Mutations in the common γ chain of cytokine receptors affecting T cell maturation due to IL-7 signal loss.
- Autosomal SCID: Caused by adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) deficiencies leading to toxic metabolite accumulation affecting lymphocytes.
- General causes include unidentified genetic mutations affecting T and B cell maturity.

Develop due to non-genetic factors acquired during life; HIV infection is a significant cause. Other causes include cancers affecting bone marrow and treatments like chemotherapy.
Key causes:
- Human Immunodeficiency Virus (HIV) leading to CD4+ T cell depletion.
- Chemotherapy and irradiation impairing leukocyte precursors.
- Immunosuppressive therapies decreasing lymphocyte function.
- Protein-calorie malnutrition and splenectomy impacting immunity.

Corticosteroids: Cause leukocyte circulation changes leading to CD4 cell depletion and inhibiting T and B cell functions.
Methotrexate: Synthetic folic acid analogue crippling DNA synthesis pathways, leading to diminished immunoglobulin production.
Cyclosporin: Severely disrupts T cell signaling through binding to immunophilins, impairing IL-2 dependent pathways.

The leading global factor for secondary immunodeficiency, particularly protein-calorie malnutrition (PCM), impairs nearly all immune system aspects due to lack of energy, essential amino acids, vitamins, and minerals (like zinc).

Tumors can produce immunosuppressive molecules, inducing regulatory T cells and myeloid suppressor cells (MSCs) that dampen anti-tumor immunity.

Significant trauma increases vulnerability to infections, potentially due to glucocorticoids released and reduced spleen function.

HIV infection causes AIDS, recognized since the 1980s as a major historic health challenge.

A retrovirus primarily targeting CD4+ T lymphocytes, reducing their numbers.
Consists of RNA within a lipid envelope, with gp120 and gp41 surface proteins facilitating cell entry by binding to CD4 and chemokine receptors.

Disease progression relates to initial viral activation and subsequent immune destruction, including both infected and uninfected T cells.
CD4+ T cell depletion leads to immune deficiencies, thus exacerbating vulnerability to infections and certain cancers.

Characterized by acute HIV syndrome and a latency phase, leading to clinical AIDS as CD4+ T cell counts fall below 200 cells per mm3.
Opportunistic infections: Primarily viral, and certain cancers such as B cell lymphomas and Kaposi's sarcoma arise due to compromised immune responses.
Dead cell clearance by macrophages may inadvertently encourage infection spread.

Treatment focuses on HIV replication control with antiretroviral therapy, specifically highly active antiretroviral therapy (HAART).
Vaccine development remains a challenge due to diverse HIV subtypes and immune induction requirements.