22. Immunodeficiencies Flashcards
(41 cards)
primary vs secondary immunodeficiency?
primary: genetic defects that result in an increased risk of infection, estimated 1 in 500 people, may or may not be life threatening. May result from defects in lymphoid maturation or activation or from defects in effector mechanisms of innate or adaptive immunity
secondary: acquired, with a recognized cause (eg AIDS, nutritional deficiencies, stress, alcohol, immunosuppressive drugs)
a deficiency in ADA leads to what?
combined deficiency of T and B cells (because needed to go from lymphoid progenitor cell to proB/proT cell)
clinical features usually present and suggesting immunodeficiency?
- chronic/recurrent infections, increased susceptibility to infections
- infections with unusual infecting agents (eg thrush and cadidiasis albicans)
- incomplete or slow response to therapy
B cell deficiencies - common infectious consequences?
pyogenic bacterial infections
T cell deficiencies - common infectious consequences?
viral and other intracellular microbial infecations (pneymocystis carinii, atypical mycobacteria, fungi)
virus-associated malignancies (EBV-associated lymphomas)
innate immune deficiencies - common infectious consequences?
variable; pyogenic bacterial infections
when to suspect immunodeficiency?
- > 10 episodes of otitis media q year
- > 2 episodes of consolidated pneumonia q year
- > 2 life-threatening infections like meninitis, sepsis
- > 2 serious sinus infections in one yera
- recurrent abscesses
- autoimmunity in children (unusual, but when they are it could be because they’re actually immunodeficient)
- dysmorphic features w/recurrent infections
- infections w/unusual organism (fungi - aspergillus, candida; pneumocystic carinii)
primary immunodeficiencies are associated with an increased incidence of what?
i. autoimmune diseases - the primary defect causes unbalanced regulation of the entire immune system, because all parts of the immune system are tightly mutually regulated.
ii. malignancy – lack of normal immune responses against tumors and oncogenic viruses.
defects causing antibody immunodeficiency disorders?
intrinsic B cell development arrest or destruction of mature B cells
clinical presentation of antibody immunodeficiency disorders
- infections w/high-grade extracellular encapsulated pathogens (staph, strep, hemophilus, pneumococcus) and chronic sinusitis, bronchitis, or pneumonia. staph and strep are relatively resistant to phagocytosis by macrophage and neutrophil. Bacteria-specific antibody is necessary to allow opsonization
- paucity of lymphoid tissue if acquired early in life
- compatible with nearly normal growth and survival into adulthood
- autoimmune diseases occur with increased frequency’
Rx: antibody replacement with pooled gamma globulin injections
transient hypoglobulinemia of infancy
infants are delayed in ability to produce Ig. Therefore, infections become apparent when maternal IgG antibodies disappear, about 6 months
- infections may not be severe
- IVIg unnecessary
- deficiency spontaneously resolves in 1st to 2nd year of life - if it does not resolve consider possbile bruton’s agammaglobulinemia or class/subclass deficiency
- Tx: DO NOTHING
common varibale immunodeficiency (CVID)
** vague, mild immunodeficiency
sporadic and familial, heterogeneous disorders with hypogammaglobulinemia, impaired antibody responses. Increased infections. Pyogenic infections, sometimes associated with autoimmunity (pernicious anemia, hemolytic anemia, rheumatoid arthritis) and malignancies (especially in children). May present late in childhood or in adults. Have mature B cells, but no plasma cells in lymphoid tissues. Multiple abnormalities, including intrinsic B cell defects, deficient T cell help, excessive T cell suppression.
- most prevalent immunodefic
- heterogenous, sporadic or familial syndrome
- manifests at any time from infancy to after 40 yo (mostly 1-5 and 16-20 years)
- NORMAL TO LOW PERIPHERAL B CELLS, BUT ABSENCE OF PLASMA CELLS, variable to low IgG, IgM, IgA
- recurrent bacterial, viral, parasitic infections; increased incidence of autoimmune disease and malignancy
- various etiology - b cell defects, deficient T cell help, or excessive suppressor T cell activity
Tx: Ig replacement or bone marrow transplant
x-linked agammaglobulinemia (XLA) / Burton’s agammaglobulinemia
Failure of B cells to mature beyond pre-B cell in marrow, caused by mutations in B cell tyrosine kinase (Reduced or absent B cells in peripheral blood and lymphoid tissues, no germinal centers, no plasma cells. T cells usually normal. Autoimmunity occurs in about 20% of patients.)
- among the more common primary immunodeficiencies; only boys affected
- BTK gene defect
- B lymphocytes don’t differentiate or mature, without mature B lymphocytes, Ab-producing plasma cells also absent. Tcells normal
- recurrent pneumonias and other bacterial sinopulmonary infections, sepsis, meningitis, diarrhea
- autoimmunity common
tx: bone marrow transplant
IgA deficiency
most common gongenital immunodeficiency, 1 in 700 people. Sporadic or inherited. Clinical course ranges from asymptomatic to severe infections of respiratory and GI tract with assocaited autoimmunity, Block (unknown type) is in differentiation of B cells to IgA secreted by plasma cells. IgM and IgG levels are normal
- many pts unaware that they have this disease
- autosomal inheritance
0 clinically may be normal or may have GI or PULMONARY infections - autoimmune disease
- MAY REACT TO IgA IN TRANSFUSIONS , SO NEED TO AVOID INFUSION OF SERUM
x-linked lymphoproliferative syndrome (duncan’s disease)
inability to eliminate EBV, leading to fulminant infectious mononucleosis, B cell tumors, and hypogammaglobulinemia. Defect is the molecules of a signaling cascade that regulates development and activation of T cells and NKT cells. Production of cytokines by CD4+ T cells, NK cell-mediated cytotoxicity; and B cell antibody production are all impaired.
- mutation in SH2D1A gene encoding SAP protein
- rare defect in immune response to EBV
- leads to severe, often deadly infectious mono, B cell lymphomas, hypogammaglobulinemia
- fail to make anti-EBV Ab, defective cytokine production, low CD4/CD8 ratio
DiGeorge’s syndrome
** immunodeficiency combined with tetany, and/or hypothyroidism, and /or craniofacial defects and/or major cardiovascular dysgenesis
(Third and Fourth Pharyngeal Pouch Syndrome) – defect in T cell maturation. Defective development of the thymus (defective T cell maturation) parathyroid glands (hypocalcemia, which causes tetany), great vessels (congenital defects) and face, and esophagus (esophageal atresia). Variable degrees of defects. Absent or reduced peripheral T cells that don’t respond normally. Antibody levels may be normal or decreased. Susceptible to mycobacterial, viral, and fungal infections. Treated by fetal thymic transplant.
- sporadic disturbed development of 3rd and 4th pharyngeal pouches before 8th week of gestation - deletion in 22 chromosome or non-genetic (teratogens)
- loss of thymus - absent or reduced T cells; mycobacterial, viral, fungal infections (severity depends on degree of defect)
- loss of parathyroids - TETANY due to hypocalcemia
- CRANIOFACIAL DEFECTS: micrognathia, hypertelorism, abnormal external ears, CARDIOVASCULAR DEFECTS, esophageal atresia, cognitive/behavioral/psych problems
- tx: thymic fetal transplant
Chronic Mucocutaneous Candidiasis
Persistent Candida infections of scalp, nails, mucous membranes
- T cell dysfunction specifically against a yeast-like fungus candida albicans due to various molecular defects
- usually present in infancy or early childhood, but a mean onset at 3 years (adult onset reported)
- candidal infection of skin, nails, and/or mucous membranes
- heterogenous gorup of conditions, but IL-17 and IL-17R deficiencies cause CMC
X-linked Hyper IgM
*high IgM levels, low levels of all other Ig, true defect in T cells (CD40L)
Immunoglobulin deficiency with increased IgM – defect in T cell-dependent B cell activation, with no heavy chain isotype switching to other Ig isotypes, with compensatory increase in IgM. Cause is mutations in gene encoding CD40 ligand (CD40L). Also may have defective cell-mediated immunity, because CD40 ligand is involved in T cell-dependent activation of macrophages. Predisposed to Pneumocystis jerovecii infections
- failure of Ig isotype switching due to mutation of CD40L gene on X chromosome - boys only
- deficiency of all Ig classes while excess IgM due to failure to switch
- primary T cell defect manifesting as antibody deficiency
- no germinal centers
activation-induced cytidine deaminase (AID) deficiency
- AR
- recurrent bacterial sino-respiratory and GI infections
- lymphoid hyperplasia
- massive germinal centers
neonatal rash in SCID
GVHD
x-linked SCID
mutations in common gene encoding cytokine receptor gamma chain, which is involved in cytokine signaling, including IL-7 signaling (which promotes lymphocyte maturation) and IL-15 signaling (which is important in natural killer cell maturation)
- lack the common gamma chain, which is shared by the IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 receptors
- reduced T cell numbers, B cell numbers not reduced
- serum IgG reduced
SCID due to ADA deficiency
ADA functions in the salvage pathway of purine degradation and catalyzes irreversible deamination of adenosine and 2’deoxyadenosine to inosine and 2’oxyinosine, respectively. Deficiency leads to accumulation of deoxyadenosine and its precursors, which have toxic effects including inhibition of DNA synthesis. Lymphocytes are particularly sensitive to ADA deficiency. Get reduction in T and B cell numbers within first year of life. Some may have normal numbers of T cells which fail to proliferate in response to antigen. Inheritance is autosomal.
- autosomal recessive, accum of metabolites that are toxic to T and B cells; reduced T and B cell numbers
- pneumonia, chronic diarrhea, skin rashes
- pseudochrondrodysplasia-defect in CARTILAGE FORMATION
SCID - PNP deficiency
Similar, but less common, is purine nucleoside phosphorylase (PNP) deficiency. Deficiency leads to accumulation of deoxyguanosisne and deoxyguanosine triphosphate, with are toxic especially to immature T cells. Strategy has been used to develop anti-T cell drugs to treat rheumatoid arthritis.
- autosomal recessive; accum of metabolites that are toxic to T but NOT B cell; reduced T and normal B cell numbers; Ig levels are normal but function impaired
SCID - reticular dysgenesis
defect at the level of the hematopoietic stem cell, causing absence of T cells, B cells, and myeloid precursors
- T, B cells, granulocytes virtually absent; the most severe SCID
- patients commonly still born or only surviv e afew days
