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Flashcards in Immunology Diseases Deck (27)
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1
Q

DiGeorge Syndrome

A

Cause:

Chromosomosal deletions of 22q11.2

General Description: conotruncal defect due to abnormal development of 3rd and 4th pharyngeal pouches of the neural crest leading to midline defects including aplasia/hypoplasia of the thymus

  • ->Cardiac issues: interrupted aortic arch, tetralogy of Fallot, ventral septal defects
  • ->Parathyroid: hypocalcemia
  • *–> Immune system: l_ow/absent T cells_, autoimmune disease; **Majority of patients have partial DGS with deficits in T cell numbers and low/normal mitogen responses, and can have normal to low antibody levels and responses to pneumococcal polysaccharide antigen

Severely affected patients susceptible to opportunistic infections such as Pneumocystis jiroveci, as well as frequent viral infections

–>Facial features: dysmorphic (low set ears, telecanthus w/ short palpebral fissues, short philtrum)

Treatment: thymis transplant, calcium supplementation, prophylactic antibodies

2
Q

Severe Combined Immunodeficiency General

A

Symptoms include: failure to thrive, candidiasis, chronic diarrhea, opportunitistic infections, (some) significant dermatitis/ecezema

Marked T cell dysfunction, T cell lymphopenia as well as lack of B cell number and/or function

small and dysplastic thymus in almost all forms

Phenotype depends on genetic defect; defects can be in lymphocyte survival, in gene rearrangement and in cytokine mediated signaling

Forms of SCID are categorized based on lymphocytes

3
Q

Forms of SCID

A
  1. T-B+NK-
    a. gc (common gamma chain), JAK3, CD45, Lck, IL-2Ralpha
    b. Half of SCID is Xlinked and due to gc chain defect
    c. T cells absent, B cells present in normal numbers but not functional
    d. These are involved in cytokine signaling
    e. 50% of SCID is Xlinked and due to γc chain defect
  2. T-B+NK+
    a. IL-7Rα, CD3γ, CD3δ, CD3ε, CD3ζ
    i. These are TCR specific or impt in Tcell proliferation
  3. T-B-NK+
    a. RAG1, RAG2, artemis, Cernunnos
    i. These are involved in T and B cell gene rearrangement
  4. T-B-NK-=ADA (adenosine deamninase deficiency)
    a. ADA, Reticular dysgenesis, PNP
    i. Metabolism or production issues not specific to lymphocytes
    b. 15-20% from ADA deficiency
    c. Defect in purine salvage pathway leading to lymphocytotoxic accumulation of adenosine and deoxyadenosine and metabolites, which inhibit DNA synthesis and repair
    d. Half of patients have skeletal findings, hearing loss, behavioral issues
4
Q

Omenn syndrome

A

I. partial defect in RAG1/2, ARTEMIS, IL-7R defect
II. SCID phenotype with erythroderma, lymphadenopathy, hepatosplenomegaly, eosinophilia, high IgE
III. Oligoclonal T cells present–>can give a normal WBC count

5
Q

SCID Treatment

A

TREATMENT
Must avoid live vaccines, and all blood products must be irradiated to prevent graft vs host disease
May be possible to replace ADA in ADA SCID patients until they can be transplanted
>95% survival if BMT within the first 3 months of life drops to 50% survival after 1 year of age

SCID SCREENING
SCID is being added to the newborn screen and is done by looking for TRECS (T cell receptor excision circles) in dried blood spots on guthrie cards by rtPCR
TRECS are episomal nonreplicative DNA circles that are excised during T cell receptor rearrangement
indicates number of naïve T cells leaving the thymus

6
Q

Bare Lymphocyte Syndrome I

A

lack of MHCI expression due to mutations in TAP1, TAP2 or tapasin genes (lack of intrathymic maturation of CD8 Tcells)

Pts have difficulty fighting viral infections (esp. respiratory–>chronic uppper respiratoy infection)

Pts do not have opportunistic infections

7
Q

Bare Lymphocyte Syndrome II

A

Rare autosomal recessive disease

Presents phenotypically like SCID w/ susceptibility to opportunistic infections but unlike SCID, cells have a normal mitogen response to PHA

Defect in transcription factors that regulate expression of MHCII leads to lack of MHCII expression–>defecetive maturation of CD4 T cells–>low Ig levels and lack of proper response to vaccinations

8
Q

Wiskott-Aldrich Syndrome

A

X linked defect in WASP gene

WASP gene regulates actin cytoskeleton of T cells and megakaryocytes

Defect leads to problems with T cell receptor signalling and T: B cell interactions and platelet formation

Symptoms: petechiae, thrombocytopenia, eczema, infection (can lead to opportunistic infections)

9
Q

Ataxia-Telangiectasia

A

AR disease due to defect in ATM gene, a key regulator of cellular response to DNA double strand breaks
Progresssive cerebellar ataxia-early
Oculocutaneous telangiectasia-late
Radiation sensitivity
Dysgammaglobulinemia, lymphopenia
low IgA, LMW IgM, increased sinopulmonary infections
Malignancy
Elevated serum AFP in 95% of pts

10
Q

X-Linked Agammaglobulinemia

A

A. Block in B cell maturation
B. Defect is in BTK (Bruton’s tyrosine kinase)
C. Usually well during first few months of life (mother’s IgG), than sick with otitis, sinusitis, pneumonia, diarrhea
D. Small or absent lymph nodes, tonsils and adenoids
E. Low or absent B cells
F. Treatment is IVIG and sometimes daily prophylactic antibiotics

11
Q

Hyper IgM Syndrome 1

A

CD 40 Ligand deficiency:
- CD40L interacts with CD40 on B cells, interaction causes B cell to proliferate and isotype switch
-Have a normal number of B cells but they can’t isotype switch
-High or normal IgM with low A, G and E
-Bacterial and opportunistic infections

-Liver disease and cryptosporidium infection
-Increased incidence of autoimmunity and cancer
-Tx is a bone marrow transplant
X linked

12
Q

Hyper IgM Syndrome 3

A

CD 40 Deficiency

  • Autosomal recessive
  • Should interact with CD40 ligand on T cells
  • Susceptible to bacterial and opportunistic infections
  • B cells can not class switch
  • Tx is IVIG and prophylactic antibiotics
13
Q

Hyper IgE Syndrome

A

A. AD-HIES (Job’s Syndrome)

a. Elevated IgE with decreased specific antibody production
b. STAT 3 mutation
c. Facial features, bone fractures, delayed shedding of primary teeth, hyperextensible joints, bacterial infections

B. AR-HIES

a. Mutation in DOCK 8 associated with reduced B and T cells
- cutaneous viral and staph infections
- cancer, atopy and anaphylaxis
b. Mutation in TYK2
- normal T and B cells
- susceptibility to mycobacteria and salmonella

14
Q

Common Variable Immunodeficiency

A

A. Reduced levels of one or more immunoglobulin and impaired antibody production.
B. Recurrent respiratory tract infections
C. More prone to autoimmune disease and lymphomas
D. TACI/ICOS mutations
E. Treatment is IVIG
F. Risk for cancer and bronchiectasis

defect in B cell differentiation

15
Q

Selective IgA Deficiency

A

A. Most common primary immunodeficiency (1:700)
B. 2/3 people with disease are asymptomatic
C. Recurrent infections, autoimmunity, allergy
D. Reason why B cells fail to switch to produce IgA is unknown
E. Treatment is prophylactic antibiotics
F. Monitor for development of CVID

16
Q

Chronic Granulomatous Disease

A

A. Defects in NADPH oxidase complex (neutrophils and macrophages can’t kill microbes)

DHR tests for NADPH oxidase
B. Multiple mutations (most common is X linked CYBB gene encoding gp91phox component of NADPH oxidase)
C. Recurrent and severe infections with:
• Staph aureus
• Serratia
• Burkholderia
• Nocardia
• Candida
• Aspergillus
D. Granulomatous inflammation (gastric outlet obstruction, colitis, hydronephrosis)
E. Diagnosed by dihydrorhodamine oxidation assay
F. Prophylaxis with Bactrim and itraconazole
G. Bone marrow transplant has been done

17
Q

Leukocyte Adhesion Deficiency

A

A. Impaired trafficking of leukocytes
B. Different types (all autosomal recessive)
• LAD 1: mutation in ITGB2 gene encodes CD18 (problem with stable adhesion of leukocyte to endothelial cell resulting in lack of ability of leukocyte to reach site of infection)

• LAD 2: mutation in GDP-fucose transporter (defect in fucosylation results in lack of ligand for E selectin that results in impaired rolling along endothelium)
C. Impaired wound healing, severe periodontitis
D. Classical presentation is omphalitis with delayed separation of the umbilical cord

E. Absence of pus formation, leukocytosis
F. Treatment is prophylactic antibiotics possible BMT for type 1, supplemental fucose for type 2

18
Q

Chediak Higashi

A

A. Partial albinism
B. Giant lysosomes
C. Defect in LYST, impaired lysosomal trafficking
D. Increased susceptibility to bacterial infections

19
Q

APS1/APECED

A

Autosomal recessive
AIRE gene mutated–> (defective negative selection of self reactive T cells)
Patients have mucocutaneous candidiasis, adrenal insufficiency and hypoparathyroidism.
Many also have type 1 diabetes, alopecia, thyroiditis
Rare (1:10000 in Finns and Sardinians)
Fatal without a bone marrow transplant

20
Q

IPEX

A

Individuals with mutations in the FOXP3 gene develop a condition known as Immunodysregulation, Polyendocrinapthy, Enterpathy, X-linked (IPEX) syndrome. IPEX patients present early in life with multiple autoimmune disorders such as type 1 diabetes, enteropathy, autoimmune skin disease and hypotheroidism

21
Q

Autoimmune Hemolytic Anemia

A

Antibodies result in destruction of target (RBCs)

–>Method: complement and FcR phagocytes

Clinical features of this disease include shortness of breath, pallor and fatigue (signs of anemia).

22
Q

Goodpasture’s syndrome

A

Noncollagenous domain of basement membrane (collage type IV) gets destroyed due to anti-GBM antibodies–>glomerulonphritis, pulumonary hemorrhage

23
Q

Autoimmune thrombocytopenic purpura

A

Antibodies target platelets; associated with bleeding problems

Txn: removal of spleen, or administration of IVIG

24
Q

Grave’s Disease

A

Antibody binds and enhances TSH receptor.

Effect: minimizez TSH and stimulates excess production of thyroid hormone. The presence of the antibody overrides the normal inhibitory feedback loop that turns off TSH production in the presence of thyroid hormones. This results in clinical hyperthyroidism

can be transmitted to the fetus, since IgG can cross the placenta. The antibodies can cause disease in the newborn but the antibodies can be removed by plasmapheresis and this cures the disease.

25
Q

Myasthenia Gravis

A

Inhibits function of acetylcholine receptor and blocks its function.

Thus when the neurons at the neuromuscular junction fire and release acetylcholine the antibodies binding to the receptor prevent the binding of the neurotransmitter and the muscle does not contract. In addition the binding of the antibody to the receptor results in internalization and degradation of the receptor and thus fewer receptors are present at the junction

26
Q

Type 1 Diabetes

A

Only beta cells targetted by autoimmune response.

Some insult (virus, remodeling during growth) to the pancreas causes beta cell damage releasing antigens that are picked up by APC and taken to the draining lymph nodes. T cells become activated and differentiate into various effector cell types . These cells migrate to the pancreas and initially Th2 and Treg cells dominate and the cells accumulate around the islet but do not invade. During this phase antibodies to insulin and other islet specific antigens can be detected in the serum, but these do not cause damage. At some point the milieu changes and becomes more inflammatory such that Th1 cells dominate and the cytokines secreted by these cells (IFN-γ, TNF-α, IL-1) cause damage to the islet cells. CD8 T cells are also activated and are induce to differentiate into effector cells by Th1 cells and they contribute by directly killing islet cells.

27
Q

Multiple Sclerosis

A

immune response targets myelin-associated proteins

Breakdown of the blood brain barrier allows escape of antigen and allows T cells to infiltrate into the CNS. APC in the brain further activate the T cells leading to influx of innate and adaptive immune cells, resulting in inflammation and demyelination. The pathogenic T cells are Th1 and Th17 cells.