Immunodeficiency Disorders מחלות חסר אימונולוגיות. 0. Origins of Immunodeficiency. Primary or Congenital ראשוני או מולד Inherited genetic defects in immune cell development or function, or inherited deficiency in a particular immune molecule
מחלות חסר אימונולוגיות
Not enough Ig or too much Ig
- B cells absent in peripheral blood.
- T cell numbers and function are normal
A syndrome characterized by very low serum IgG, IgA and IgE but extremely high levels of IgM.
X-linked - CD154 (CD40 Ligand) Deficiency
Autosomal Recessive -Activation-Induced Cytidine Deaminase Deficiency (AICD)
Diagnosis - Males become symptomatic after 6-9 months. Prone to pneumonia, have profound neutropenia, and very small lymph nodes and tonsils. B cells and T cell numbers are normal.
Molecular Defect - mutation in CD154 or CD40 Ligand.
- found on the surface of activated helper T cells. Interacts with CD40 on surface of B cells.
- Cross-linking of CD40 by CD40L in the presence of cytokines causes B cells to undergo proliferation and isotype switching.
Defective T-B interaction in
Hyper IgM Immuonodeficiency
Male and Female
Diagnosis - Serum IgG, IgA, and IgE are very low. Serum IgM elevated and polyclonal.
-Patients are generally older and not susceptible to pneumonia.
-Normal numbers of B cells but are not able to class-switch in presence of T cells
Molecular Defect - mutations in activation-dependent cytidine deaminase (AID).
Agammaglubulinemia - Monthly injections of antibody, intravenous gammaglubin “IVIG”
Hyper IgM Syndrome - Bone marrow
transplant at early age. IVIG,
management of infections with antibiotics
A disease that results from hypoplasia (partial loss) or aplasia (complete loss) of thymus and parathyroid glands, therefore no T cells. Relatively common (1/4000 live births), affect both male and female
Diagnosis - Spectrum of developmental abnormalities: cardiac outflow abnormalities (congenital heart disease) , hypoplasia of the parathyroid and thyroid glands, cleft palate and unusual facies. Normal Ig levels.
Molecular Defect - Gene Tbx1 (transcription factor) on chromosome 22q11 is defective in most cases. Causes defects in 3rd and 4th pharyngeal pouches during embryogenesis
Clinical spectrum and effect on thymus is highly variable
Complete (rare) : Severe T cell lymphopenia. Increased susceptibility to pneumonia (P. carinii), oral candidiasis, diarrhea, failure to thrive.
Mild (common) : present in adults as chronic sinusitis/ bronchitis
Facies: Micrognathia, low set ears, anti-mongoloid slant to eyes, fish-shaped mouth, hypertelorism, narrow philtrum
e.g. the IL-2R family utilizes the same g chain.
Neutrophils require a set of enzymes to produce reactive oxygen species to destroy bacteria after their phagocytosis. Together these enzymes are termed "phagocyte NADPH oxidase" (phox). Defects in one of these enzymes can all cause CGD of varying severity, dependent on the defect. There are over 410 known defects in the enzyme complex
Absence of respiratory burst (conversion of intracellular oxygen to hydrogen peroxide, oxidized halogens, superoxide and hydroxyl radicals) in neutrophils and monocytes-impaired bactericidal killing
Chronic inflammation with a characteristic pattern of a central area of phagocytic cells surrounded by activated lymphocytes.
Macrophages fuse to form giant cells in the center
Serves to “wall off” pathogens that resist destruction.
In CGD get continuous granuloma formation because neutrophils cannot clear microbes
Nasal inflammation/cellulitis and neck granuloma in an X-linked CGD patient.
X linked SCID (common gamma chain)
T cell deficiency (absence of thymus DiGeorge’s syndrome)
Antibody Deficiencies XLA (Btk-/-) Hyper IgM (CD40L-/-)
Deficiencies in Phagocytosis/killing:
Respiratory Burst (CGD)