Primary Immunodeficiency Syndromes (PIDs)

• Primary Immunodeficiency Syndromes (PIDs) are rare congenital disorders affecting the immune system.
• Prevalence ranges from 1:500 to 1:500,000 in the general population, varying by country.
• PIDs result from genetic defects affecting innate immunity (phagocytes, NK cells, complement) or adaptive immunity (B and T lymphocytes).
• Immunodeficiencies manifest as Serious, Persistent, Unusual, or Recurrent infections (SPUR), along with autoimmunity, inflammation, allergy, and malignancy.
• The type of infection indicates the deficient part of the immune system.
• Recurrent pyogenic bacterial infections suggest defects in antibody, complement, or phagocyte function.
• Recurrent viral infections suggest a defect in T lymphocytes.
• Primary immunodeficiencies are classified into B-cell/humoral, T-cell/cellular, phagocyte defects, and complement system abnormalities.

Primary B-Cell Immunodeficiency Diseases

• These diseases involve defective B cell development or deficiencies in antibody subclasses.

Bruton X-Linked Agammaglobulinemia (XLA)

• XLA is caused by the failure of pre-B cells to differentiate into B cells, resulting in the absence of antibodies in the blood.
• It is an X-linked disorder seen mainly in males, presenting in infancy (7-9 months) as maternal antibody levels decline.
• Molecular pathogenesis involves a genetic defect on the X chromosome (Xq21.22) that inactivates B-cell tyrosine kinase (BTK), crucial for B-lymphocyte maturation.
• Clinical features include recurrent pyogenic bacterial infections (staphylococci, Haemophilus influenzae, Streptococcus pneumoniae), mucosal tract infections, enterovirus infections affecting the CNS and joints.
• Other manifestations are absent or decreased B cells in circulation, low immunoglobulin levels, and absence of plasma cells.
• T cell responses are typically normal.
• Treatment involves intravenous immunoglobulin injections.

Common Variable Immunodeficiency (CVID)

• CVID is a heterogeneous group of disorders with hypogammaglobulinemia affecting all or some antibody classes.
• It occurs sporadically or is inherited, with onset at age 15-35 years, affecting both males and females.
• Defective antibody production results from B cell defects or deficient T helper cell activation.
• Patients have normal mature B cell numbers but lack plasma cells, suggesting a block in B cell differentiation.
• Abnormality in BAFF cytokine receptor or ICOS molecule explains less than 10% of cases; the rest are unknown.
• Clinical features include impaired antibody responses, increased infections (pneumonia, bronchiectasis, sinusitis, GI infections), decreased serum IgA and IgG, with normal or low IgM.
• There is a higher risk for autoimmune disorders (hemolytic anemia, neutropenia, thrombocytopenia) and gastric cancers/lymphomas.
• Treatment is intravenous immunoglobulin injections.

Selective IgA Deficiency

• This is the most common primary immunodeficiency; characterized by normal IgG and IgM but low IgA in serum and secretions.
• Weakened mucosal defenses due to low IgA lead to infections in the respiratory, gastrointestinal, and urogenital tracts.
• Molecular pathogenesis involves deletions or defects in chromosome 18 or defects in the BAFF receptor, resulting in the inability to synthesize and secrete IgA.
• Clinical features include being asymptomatic early in life, respiratory/GI infections, allergies, autoimmune diseases.
• 20% of individuals develop antibodies to IgA, leading to anaphylactic reactions to IgA-containing blood products.
• IgA cannot be replaced therapeutically; treatment includes prompt antibiotics and immunization against respiratory pathogens.

Hyper-IgM Syndrome

• Patients produce normal/high levels of IgM but lack IgG, IgA, and IgE production, diagnosed at age 1-2 years.
• Molecular pathogenesis involves a defective "switch" to other heavy-chain isotypes due to the disrupted interaction of CD40 receptor on B cells with CD40 ligand on T cells.
• The most common genetic abnormality is mutation of the gene encoding CD40L on the X chromosome (70% of cases, X-linked).
• Clinical phenotype includes recurrent pyogenic infections due to low IgG, susceptibility to Pneumocystis jirovecii pneumonia, and autoimmune diseases.
• Circulating B cells bear only IgM and IgD.
• Replacement immunoglobulin therapy and bone marrow transplantation are the treatments of choice.

Primary T-Cell Immunodeficiency Diseases

• These diseases involve defects in T-cell development and function.

DiGeorge Syndrome

• Congenital thymic aplasia occurs where the thymus does not develop normally.
• Recognized in infants with congenital heart defects and hypocalcemia (hypoparathyroidism).
• Molecular Pathogenesis: DiGeorge syndrome is a component of the 22q11 deletion syndrome.
• Defective development of the third and fourth pharyngeal pouches impacts thymus, parathyroid glands, and heart development.
• Absence of the thymus interrupts T-cell maturation.
• Clinical features include hypocalcemia, congenital heart disease, recurrent infections (viruses, bacteria, fungi, protozoa), and lack of immune response after T-dependent antigen immunization.
• Thymic tissue transplantation corrects the immunologic defect.

Severe Combined Immunodeficiency Syndrome (SCID)

• SCID is a heterogeneous group of disorders caused by deficiencies in T-cell and B-cell development and function.
• Molecular Pathogenesis: 50% of X-linked cases are due to mutations in the gene encoding the common γ chain for IL-2, IL-4, IL-7, IL-9, and IL-15 receptors.
• 40-50% of autosomal recessive cases are due to mutations in adenosine deaminase (ADA), impacting purine metabolism and causing toxic metabolite accumulation.
• Pathological Findings include life-threatening infections soon after birth, wasting/failure to thrive, and lack of thymic development.
• Other findings are lymphopenia, hypoplastic lymphoid tissues, and lack of CD3+, CD4+, CD8+ and lymphocyte response to antigens.
• SCID is fatal without immune system reconstitution via hematopoietic stem cell transplantation.
• Gene therapy, intravenous immunoglobulin injections, and supportive care are also part of the treatment.

Wiskott-Aldrich Syndrome

• Wiskott-Aldrich syndrome is an X-linked recessive disease characterized by thrombocytopenia, eczema, and susceptibility to recurrent infections.
• Molecular pathogenesis involves mutations in the gene encoding Wiskott-Aldrich syndrome protein, affecting membrane receptor-cytoskeleton linkage, cell morphology, activation, and cell-cell adhesions.
• Clinical phenotype and management includes bleeding, recurrent bacterial infections, allergic reactions, and being prone to malignant lymphomas.
• Other manifestations are progressive age-related T lymphocyte depletion and lack of antibody responses to polysaccharide antigens.
• Treatment is bone marrow transplantation.

Primary Phagocyte Abnormalities

• Neutrophils ingest, kill, and digest microorganisms; failure leads to infection.
• Defects are quantitative (neutropenia) or qualitative (neutrophil dysfunction).
• Infections are recurrent, prolonged, poorly responsive to antibiotics, often staphylococcal, and involve skin/mucous membranes.
• Complications include suppurative lymphadenopathy.

Defects in Leukocyte Adhesion

• Leukocyte adhesion deficiency type 1 (LAD-1) leads to defective CD18 β subunit synthesis, impairing leukocyte adhesion/migration and phagocytosis.

Defects in Microbicidal Activity

• Chronic granulomatous disease involves failure to produce functional NADPH oxidase, leading to impaired oxygen-dependent killing mechanisms.
• Microbes are surrounded by activated macrophages, forming “granulomas”.
• CGD presents in the first 3 months of life as severe skin sepsis.

Defects in Phagolysosome Formation

• Chédiak-Higashi syndrome is an autosomal recessive disease with disordered intracellular trafficking of organelles, impairing lysosome-phagosome fusion.

Genetic Deficiency of Complement Proteins

• Complement components play roles in inflammatory and immunologic responses.
• Hereditary deficiencies result in impaired immune response.
• C2 deficiency is the most common and is associated with increased bacterial/viral infections, often without clinical manifestations.
• C3 deficiency results in susceptibility to pyogenic bacterial infections.
• Deficiencies of late components (C5 to C9) result in recurrent Neisseria infections.

Findings that point to an underlying immunodeficiency

• Recurrent infections, with diverse pathogens after completing antibiotic.
• Infection caused by the infectious agent, unusual age of onset, unexpected site of infection, severity and failure to treatment .
• Abnormal tissue reaction: example granuloma formation in staphylococcal infection.
• Failure of an infant to gain weight or grow normally and family history of primary immune deficiency.
• Conditions associated with primary immunodeficiency syndrome: example hypoparathyroidism .