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Primary Immune Deficiencies (B-Cell Disorders (IgA Deficiency (Etiology…
Primary Immune Deficiencies
B-Cell & T-Cell Combined Disorders
Severe Combined Immunodeficiency Disorders (SCID)
Etiology & Pathogenesis
-Characterized by absence or dysfunction of T cells affecting both cellular & humoral adaptive immunity
-Vary in severity & clinical features
-Affects boys more often than girls
-Involves deficiency in enzymes needed for immune cell functioning & causes accumulation of toxic metabolites of purine or adenisine
-Can involve increased B-Cell numbers, but said B-Cells cannot function normally due to poor antibody production (Decreased IgG, IgM, and IgA synthesis)
-Considered a medical emergency (TB- having a worse overall outcome than TB+)
B-Cell Presence
T-B+
-T-B+ Have mutations in 1 out of 4 CD3 genes
-X-linked recessive type is most common type; cases lack circulating T-cells but have normal to increased number of B-Cells
T-B-
-T-B- Have mutations in recombination activating genes 1 or 2 (RAG1 or RAG2)
-Both are involved in the process of antigen
receptor assembly
3 Major Types
1. Classical
-AKA "Reticular Dysgenesis"
-Most severe form
-Defined by failure of all white blood cell development (both lymphocytes & granulocytes)
2. Atypical
3. Omenn Syndrome
Clinical Manifestations & Treatment
-Cases generally have small, hypoplastic thymus glands (Indicative of poor/absent T-Cell development)
-Cases are vulnerable to sepsis, opportunistic infections w/ pathogens (Candida albicans) or viruses (Herpes)
-Cases often have thrush, severe Candida diaper dermatitis, or infections causing otitis, pneumonia & diarrhea
-Treatments include:
Hematopoietic stem cell transplants
Chemotherapy conditioning regimens
Long-term immunoglobulin therapy
Enzyme replacement therapy
Gene therapy
B-Cell Disorders
IgA Deficiency
Etiology & Pathogenesis
-Most common B-Cell primary immunodeficiency disorder
-Characterized by failure of IgA-bearing lymphocytes to become plasma cells
-Results in lack of secretory IgA in the serum
-Can be an autosomal recessive/dominant disease
-B-Cell level is normal, but is a lack of B-Cell response to interleukins
Clinical Manifestations & Treatment
-Cases are prone to respiratory, GI & GU infections, they also tend to have many autoantibodies
-Cases have a high incidence of vascular, endocrine & collagen autoimmune diseases
-Involves severe allergies to blood/blood products containing IgA
-Treatment includes prevention of infection & management of infection w/ antibiotics
Bruton X-Linked Agammaglobulolinemia
Etiology & Pathogenesis
-AKA "Congenital Hypogammaglobulinemia"
-The first immunodeficiency disorder identified
-A genetic B-Cell disorder caused by lack of normal B-Cell development in the bone marrow
-Linked to a mutation of the btk gene; occurs in a cytoplasmic signal-transducing molecule encoded by the btk gene
-Causes decreased serum concentrations of IgG & no detectable IgM or IgA
-Involves a decreased number of CD4 memory T-Cells (caused by lack of B-Cells)
-Characterized by recurrent bacterial infection & profound hypogammaglobulinemia resulting from decreased numbers of circulating B-Cells
Clinical Manifestations & Treatment
-Manifestations include frequent infections often attributable to Haemophilus influenzae & Streptococcus pneumoniae (Results in pneumonia, otitis media, meningitis, sinusitis & septicemia)
-Recurrent infections lead to tissue destruction & injury
-Most children w/ disorder DO NOT survive to adulthood
-If children w/ disorder survive to adulthood, they commonly get diagnosed w/ chronic lung disease & large joint arthritis
-Treatments include:
Antibiotic theraoy
Prophylactic antibiotics
Curative hematopoietic stem cell-based gene therapy
T-Cell Disorders
DiGeorge Syndrome
Etiology & Pathogenesis
-AKA "Deletion Syndrome" or "Thymic Hypoplasia"
-Associated w/ total/partial loss of thymus gland function
-Caused by a chromosomal 22q11.2 deletion
-Most common deletion syndrome in newborns
-Aplastic/hypoplastic thymus is unable to assist in T-Cell maturation; T-Cells are deficient while B-Cells are normal
Clinical Manifestations & Treatment
-A congenital disorder of fetal organ development
-Associated w/ other congenital problems (Developmental delay, cardiac & great vessel anomalies, hypothyroidism)
-Partial loss of function may not create trouble in dealing w/ infections
-Most effective treatment is thymic transplantation w/ therapies for management tailored specifically to the patient
Chronic Mucocutaneous Candidiasis
Etiology & Pathogenesis
-A T-Cell disorder caused by 2 different etiologies
-Characterized by a selective deficiency of cell-mediated immunity against Candida albicans
-T-Cells are unable to produce the correct cytokines needed for cell-mediated immunity to C. albicans; causes persistent/recurrent severe skin, nail & mucuous membrane infections w/ C. albicans
-B-Cell & T-Cell functions are usually normal, except for inability of T-cells to respond to Candida infections
2 Causes
1) Autosomal
recessive
deficiency in Interleukin-17 Receptor A (IL-17RA); causes complete lack of cellular responsiveness to cytokines IL-17A and IL-17F
2) Autosomal
dominant
deficiency of IL-17F; only allows partial cytokine activity
Clinical Manifestations & Treatment
-Treatment goal is to reduce the severity of the skin & mucous membrane infection & decrease disfigurement from infection & scarring
-Most effective treatment is antifungal therapy
-Associated w/ Autoimmune Polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED)