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hdid 1 > 22. Immunodeficiencies > Flashcards

22. Immunodeficiencies Flashcards

1
Q

primary vs secondary immunodeficiency?

A

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)

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2
Q

a deficiency in ADA leads to what?

A

combined deficiency of T and B cells (because needed to go from lymphoid progenitor cell to proB/proT cell)

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3
Q

clinical features usually present and suggesting immunodeficiency?

A
  • chronic/recurrent infections, increased susceptibility to infections
  • infections with unusual infecting agents (eg thrush and cadidiasis albicans)
  • incomplete or slow response to therapy
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4
Q

B cell deficiencies - common infectious consequences?

A

pyogenic bacterial infections

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5
Q

T cell deficiencies - common infectious consequences?

A

viral and other intracellular microbial infecations (pneymocystis carinii, atypical mycobacteria, fungi)

virus-associated malignancies (EBV-associated lymphomas)

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6
Q

innate immune deficiencies - common infectious consequences?

A

variable; pyogenic bacterial infections

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7
Q

when to suspect immunodeficiency?

A
  • > 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)
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8
Q

primary immunodeficiencies are associated with an increased incidence of what?

A

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.

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9
Q

defects causing antibody immunodeficiency disorders?

A

intrinsic B cell development arrest or destruction of mature B cells

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10
Q

clinical presentation of antibody immunodeficiency disorders

A
  • 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

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11
Q

transient hypoglobulinemia of infancy

A

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
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12
Q

common varibale immunodeficiency (CVID)

A

** 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

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13
Q

x-linked agammaglobulinemia (XLA) / Burton’s agammaglobulinemia

A

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

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14
Q

IgA deficiency

A

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
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15
Q

x-linked lymphoproliferative syndrome (duncan’s disease)

A

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
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16
Q

DiGeorge’s syndrome

A

** 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
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17
Q

Chronic Mucocutaneous Candidiasis

A

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
18
Q

X-linked Hyper IgM

A

*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
19
Q

activation-induced cytidine deaminase (AID) deficiency

A
  • AR
  • recurrent bacterial sino-respiratory and GI infections
  • lymphoid hyperplasia
  • massive germinal centers
20
Q

neonatal rash in SCID

A

GVHD

21
Q

x-linked SCID

A

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
22
Q

SCID due to ADA deficiency

A

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
23
Q

SCID - PNP deficiency

A

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
24
Q

SCID - reticular dysgenesis

A

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
25
Q

SCID with MHC deficiency

A

Class II deficiency = bare lymphocyte syndrome, mutations in genes encoding transcription factors essential for class II expression, which leads to failure of antigen presentation to CD4 cells. Class I deficiency - decreased CD8 T cells, in some cases caused by mutations in the TAP1 or TAP2 subunit of the TAP (transporter associated with antigen processing).

26
Q

Defects in T cell activation

A

includes mutations in the CD3 epsilon or gamma chains, mutations in ZAP-70, reduced synthesis in IL-2 or IFN- because of defects in transcription factors, lack or IL-2 receptors. Uncommon, sporadic or familial. like JAK-3 mutations

27
Q

Omenn Syndrome

A

mutations in either Rag1, Rag2, or ARTEMIS with residual functioning preserved; few oligoclonal T cells present, they are autoreactive and produce Th2 cytokines; very low B cells but high levels of IgE. Do NOT confuse with Job Syndrome, a hyper-IgE condition resulting from a defect of STAT3.

Rx - Bone marrow transplantation, gene therapy, transfusions in some cases.

  • AR Rag1/Rag2 or Artemis (necessary for VDJ recombination): mutations that impair but do not completely abrogate their fucntion (minimal residual functioning preserved)
  • SCID w/oligoclonal autoreactive T lymphocytes present that produce IL-4 and IL-5
  • B cells virtually absent, but IgE and eosinophils elevated
  • autoimmune aspect manifests as GVHD, combined with SCID and Th2 activation: diffuse erythrodema with skin desquamation and alopecia, multiple lymph node enlargement, hepatosplenomegaly, chronic diarrhea, growth retardation, and recurring fungal and viral infections
  • artemis deficiency = radiosensitive Omenn
28
Q

Job syndrome

A

NOT A SCID but a rare AD mutation in STAT3

  • recurrent sinopulmonary infections, skin infectoins, deep subQ abscesses (biblical Job) mostly due to s. aureus
  • very high levels of IgE - hyperimmunoglobulinemia E syndrome
  • coarse facies, retained primary teeth, noneruption of permanent teeth, double rows of teeth with both primary and permanent intermixed teeth
29
Q

omenn vs job?

A

both hyper IgE

omenn is newborns
Job is adults with anatomic differences (coarse facies and teeth problems)

30
Q

wiskott-aldrich syndrome

A

immunodeficiency, thrombocytopenia, eczema

  • XLR, genetic defect in a protein called WASp (wiskott-aldrich syndrome protein)
  • gene on X chrom, expression limited to cells of hematopoetic origin. Protein normally regulates ACTIN CYTOSKELETON OF LYMPHOCYTES AND PLATELETS; participates in cell growth, endocytosis, exocytosis, and cytokinesis
  • T cell deficit, often also a B cell deficit - susceptible to polysaccharide-coated bacteria (strep pneumoniae, haemophilus influenzae, staphylococcus aureus)
  • petechiae and echymoses of the skin and oral muchosa
  • rarely survive beyond childhood

X-linked, eczema, thrombocytopenia (reduces platelets), and increased infections. Inability to produce antibodies in response to T cell-independent polysaccharide antigens. Infections with encapsulated pyogenic bacteria. Reduced numbers of lymphocytes, which are small. Defect is in a cytoplasmic adapter molecule that interacts with small G proteins of the Rho family that regulate actin cytoskeleton. Reduced expression of cell surface glycoproteins, including sialophorin. Get interference with leukocyte trafficking to sites of infection.

31
Q

ataxia-telangiectasia

A

IF you give them an x-ray you will give cancer because RADIOSENSITIVE
- mom brings in kid w/movements and telangiectasia of eyes

autosomal recessive, with ataxia (abnormal gait), telangectasia (vascular malformations), neurologic deficits, tumors (defective DNA repair), and immunodeficiency, both T and B cell. May have IgA and IgG2
deficiency. Mutation in gene encoding phospatidylinositol-3-kinase, which participates in T cell activation by antigen.

  • mutations in a gene encoding a protein kinase that plays a role in signaling and repair of DNA damage (ATM - ataxia, telangiectasia, mutated)
  • AR
  • cerebellar atrophy w/ ataxia and choreoathetosis, progressive dysarthria, wheelchair bound early in life
  • ocular telangiectasia
  • EXTREME RADIOSENSITIVITY, sterility, tumors, and IMMUNODEFIC
  • decreased or absent IgA (recurrent respiratory infections)

Tx: IVIg

32
Q

clinical presentation of phagocytic defects

A

bacterial and fungal infections, few viral or protozoan infections. Prominent skin infections, chronic osteomylitis draining lymph nodes

33
Q

therapy for phagocytic defects?

A

therapeutic and prophylactic antibodies, interferon-gamma, drain abscesses

34
Q

chronic granulomatous disease

A

are usually X-linked, mutations in genes encoding components of the phagocyte NADPH oxidase enzyme, including cytochrome b558. Defective production of superoxide anion, which is a major microbicidal mechanism in phagocytes. Defect in innate immunity.

  • x-linked defect in phagocytic cells
  • mutations in phagocyte NADPH oxidase system resulting in defective production of superoxide (O2-) and H2O2 that are normally involved in killing bacteria (oxidative burst)
  • leukocytes fail to kill bacteria in vitro
  • early onset by 2-5 y/o
  • severe recurrent fungal and bacterial infections, freq fatal
  • granulomas of the skin, GI tract, and GU tract
35
Q

chediack-higashi syndrome

A

defect in NK cells and other lymphocytes. Increased fusion of cytoplasmic granules, affects lysosomes in neutrophils and macrophages, causing increased risk of infection. NK cells function abnormally, probably because of an abnormality in their cytoplasmic granules. Infections, albinism, nerve defects, and bleeding disorders due to platelet defects.

  • AR defect of LYST gene (lysosomal trafficking)
  • lysosomal defect of phagocytes (neutrophils, macrophages) and other cells; also defect in polymerization of microtubules
  • immunodeficiency (pyogenic infectsion like strep/staph affecting respiratory tract and skin)
  • abnormal function of platelets: bleeding tendency, easy bruisability
  • oculocutaneous albinism: hypopigmentation of the eyes, skin, and hair
  • progressive neurologic dysfunction
36
Q

Leukocyte adhesion deficiency (LAD)

A

Wiskott aldrich: eczema, younger, polysaccharide coated bacteria, x-chromosome

Chediak Higashi: albinism, neurologic dysfunction, autosomal recessive

both present with bleeding disorders

37
Q

wiskott-aldrich syndrome vs chediak-higashi syndrome

A

i. Defects in CD18 (beta chain of beta2 integrins) or fucosyltransferase enzyme required for synthesis of sialyl-Lewis X component of E-selectin and P-selectin. Recurrent bacterial and fungal infections, no pus.

  • type I: defect in LFA-1/CD18 (beta 2 integrin) - loss of expression on lymphocytes, macrophages, and neutrophils
  • type II: defect in fucosyltransferase resulting in loss of carb ligand for P-selectin and E-selectin on leukocytes
  • leukocytes fail to traffic to sites of infection, leading to infections, poor wound healing
  • both are rare - type I patients succumb to infections before 2 years of age, type II have better survival, but severe growth and mental retardation (neurolog problems)
38
Q

separating hyper IgM diseases?

A

CD40L defect: boys only, no germinal centers

AID defect: boys and girls, large germinal centers

39
Q

separating hyper IgE diseases?

A

Omenn: usually an infant (SCID), B cells absent or very low

Job: often older pt, retained primary teeth and non-erupted permanent teeth, B cell counts normal

40
Q

separating radiosensitivity immunodeficiencies?

A

artemis (radiation-sensitive Omenn) vs ATM (ataxia telangiectasia)

artemis:hyper IgE, form of SCID

ATM: ataxia, ocular telangiectasia, dysarthria

41
Q

MHC I vs MHC II deficiency:

A

I: decreased CD8 T cells - intracellular infections more prevalent

II: no antigen presentation to CD4 so more severe (SCID like?)

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