Immune Deficiency Syndromes Quiz

Immune Deficiency Syndromes

• Immune deficiencies encompass a range of conditions, impacting the body's ability to fight infections.
• These deficiencies can be acquired (e.g., HIV, chemotherapy) or genetic/congenital.
• A common manifestation is recurrent infections, frequently presenting in infancy.
• Several specific immune deficiency syndromes are discussed, each with unique characteristics, including X-linked agammaglobulinemia (Bruton's), Selective IgA deficiency, Common Variable Immunodeficiency (CVID), Thymic Aplasia (DiGeorge Syndrome), Hyper-IgE Syndrome, Chronic mucocutaneous candidiasis, SCID, and more.

X-linked Agammaglobulinemia (Bruton's)

• Inherited in an X-linked manner.
• B cell precursors fail to develop into mature B cells.
• Light chains are absent, impacting antibody production. A defect in the Bruton tyrosine kinase (BTK) gene underlies this condition.
• Symptoms usually appear around 6 months of age due to the waning of maternal antibodies.
• Recurrent respiratory bacterial infections, enteroviruses (echo, polio, coxsackie), and Giardia are common infections.
• Key diagnostic findings include absence of mature B cells (CD19, CD20, BCR) in peripheral blood and underdeveloped germinal centers of lymph nodes. Antibodies of all classes are absent. Treatment involves IVIG therapy.

Selective IgA Deficiency

• A relatively common condition (~1 in 600).
• The exact mechanism is unknown, but defective IgA B-cells play a role.
• Most affected individuals are asymptomatic.
• Symptoms may include recurrent sinus, pulmonary, or other infections, and recurrent diarrheal illness (from Giardia).
• Blood transfusions may trigger anaphylaxis due to IgA in blood products, which triggers antibody production in affected individuals.
• IgA-deficient patients often have additional autoimmune disorders like SLE and RA (20–30%).
• Diagnosis is based on a serum IgA level below 7 mg/dL, with normal IgG and IgM levels. Treatment typically involves prophylactic antibiotics and IVIG. A false positive result of the $\beta$-HCG test is a frequent finding, due to heterophile antibodies produced in the deficiency.

Common Variable Immunodeficiency (CVID)

• A condition where B-cell maturation is defective leading to an absence of antibodies.
• Many genetic causes exist, though a specific genetic mutation is frequently not established.
• Patients often present in their late teens or twenties.
• Features include normal B cell counts, but absence of antibodies, as well as recurrent respiratory infections, enteric infections (e.g., Giardiasis), and enteroviruses. The condition may be accompanied by autoimmune disorders like RA or lymphoma.
• Treatment involves IVIG therapy

Thymic Aplasia (DiGeorge Syndrome)

• Caused by a deletion on chromosome 22q11, not familial.
• Characterized by the incomplete development of the thymus and other affected structures, leading to a lack of T cells.
• Presents with a triad of symptoms:
  • Loss of thymus (and thus T-cells), leading to recurrent infections
  • Loss of parathyroid glands, resulting in hypocalcemia and tetanic seizures.
  • Congenital heart defects (conotruncal)
• Other common manifestations include abnormal aortic arch, truncus arteriosus, tetralogy of Fallot, and ASDs/VSDs.
• Key findings include absence of the thymus shadow on chest X-ray in infants. and severely underdeveloped T-cell structures in lymph nodes and spleen. Treatment may include thymic transplantation or hematopoietic cell transplantation.

Hyper-IgE Syndrome (Job's Syndrome)

• A rare syndrome characterized by immune dysregulation, skin and bone issues.
• Patients commonly have defective CD4+ Th17 cells (and thus IL-17). This leads to a loss of attraction of neutrophils, and STAT3 signalling pathway defects.
• A characteristic feature is increased IgE levels. This leads to recurrent infections without fever, a rash, and skin abscesses (staph skin lesions that lack warmth/redness).
• Associated abnormalities often include craniofacial abnormalities (broad nasal bridge) and retained primary teeth.
• Diagnosis based on elevated IgE and low IFN-$\gamma$ levels.

Chronic Mucocutaneous Candidiasis

• Characterized by a defect in the AIRE gene, which regulates immune function in the thymus.
• AIRE function #1 is associated with the Dectin-1 receptor response to Candida antigens, which, absent or faulty, lead to recurrent candidal infections.
• AIRE function #2, defective, promotes defective self-antigen presentation to T-cells (negative selection) and a lack of, or faulty, autoimmune T cells. This can be accompanied by endocrine dysfunction (parathyroid and/or adrenal).
• T-cell dysfunction is characterized by a deficiency in Th1 cytokines (IL-2 and IFN-γ) and increased IL-10, suggesting a cell-mediated defect. This often results in recurrent thrush, and skin/mucous membrane infections.

SCID (Severe Combined Immunodeficiency)

• A severe immunodeficiency affecting both cell-mediated and humoral immunity.
• Typically arises from a primary T-cell problem, with B-cell and antibody deficiencies often a secondary issue.
• Involves loss of T-cell/B-cell areas in lymphoid tissue, and the absence of thymic shadow.
• Affected individuals are highly susceptible to infections (viral, fungal, bacterial and also thrush, diaper rash and failure to thrive, in babies). They often die without a bone marrow transplant.
• Most common forms are X-linked (boys) with a mutation in the γ subunit of the cytokine receptor gene IL2RG, though adenosine deaminase (ADA) deficiency is another cause.
• In newborn screening, maternal T-cells can falsely increase T cell counts. The presence of TRECS (T cell receptor excision circles) and the absence of a thymic shadow are additional diagnostic clues.

Ataxia Telangiectasia

• A genetic disorder caused by a defect in the ATM gene on chromosome 11.
• This mutation results in an inability to repair DNA, specifically double-stranded breaks, often due to ionizing radiation, leading to hypersensitivity.
• Characterized by a complex mix of symptoms and findings that include nervous system issues (ataxia), skin issues (telangiectasias), and an increased susceptibility to infections and malignancies (e.g., lymphomas). The condition typically begins with gait and balance problems.
• Symptoms typically appear in childhood. Cerebellar atrophy, the presence of telangiectasias (dilated capillaries/blood vessels), and low levels of several immunoglobulins (especially IgA and IgG) are common features. Increased AFP is often observed.

Hyper-IgM Syndrome

• A disorder characterized by defective class switching of B cells, specifically, a failure of B-cell (CD40) to interact properly with T-cells (CD40L). This usually stems from a T-cell dysfunction.
• 70% of cases involved defective CD40L (gene), and is typically X-linked.
• Diagnostic indicator is an elevated IgM level coupled with the absence of other immunoglobulins. Characterized by recurrent bacterial infections, in infancy. The infections are commonly caused by encapsulated bacteria like S. pneumo and H. Flu, and also opportunistic infections like Pneumocystis, Cryptosporidium, and Histoplasmosis are possible.

Wiskott-Aldrich Syndrome (WAS)

• An X-linked immunodeficiency disorder due to a WASP gene defect. The WAS protein is needed for cytoskeleton maintenance in cells, particularly T cells.
• This inability to form "immunological synapses" means T cells don't interact correctly with antigen-presenting cells.
• Clinical symptoms frequently include eczema, thrombocytopenia (low platelets), and recurrent infections. Symptoms often become worse with age.
• Treatment usually involves bone marrow transplantation.

Leukocyte Adhesion Deficiency (LAD)

• A genetic autosomal recessive disorder, specifically affecting the CD18 protein, which is part of integrins (adhesion molecules), preventing proper migration of neutrophils (and other immune cells) into infected areas.
• A critical feature is the delayed shedding of the umbilical cord, and often presenting omphalitis infection (stump infection).
• Significant clinical manifestations include recurrent bacterial infections, and high WBC counts (neutrophilia) during episodes of infection and inflammation.

Chediak-Higashi Syndrome

• A rare disorder involving a defect in the lysosomal trafficking regulator (LYST) protein. The failure of lysosomes (organelles containing enzymes) to fuse properly with phagosomes (vesicles containing engulfed material) negatively impacts the ability of white blood cells to perform their killing functions.
• Presenting features include recurrent bacterial infections, including frequent episodes with staphylococci and streptococci infections. Oculocutaneous albinism (including fair skin, light coloured hair and light colored eyes) is a common indicator of the disease. Children who survive are frequently wheelchair bound due to neuro impairment.

Chronic Granulomatous Disease (CGD)

• A disorder in which phagocytes cannot produce the reactive oxygen species H₂O₂ as an antimicrobial defense. This stems from a defective NADPH oxidase. Catalase-negative bacteria (such as Staph aureus, Pseudomonas, Serratia, Nocardia) will already produce H₂O₂, while those positive for catalase can be destroyed because the host lacks H₂O₂ for their destruction. Defects in NADPH results in recurrent bacterial infections.
• A diagnostic test for CGD is the Nitroblue tetrazolium test, which assesses the presence and activity of NADPH oxidase production.

Test your knowledge on immune deficiency syndromes, including both congenital and acquired conditions. This quiz explores various specific syndromes like X-linked agammaglobulinemia and others, helping to understand their characteristics and symptoms. Perfect for students and healthcare professionals alike!