First Aid, Chapter 8, Immunologic Disorders, Cellular or Complex Immune Deficiencies Flashcards
Is ataxia-telangiectasia inherited or a mutation? What is the gene?
ATM; Ataxiatelangiectasia, mutated
What are the infections or clinical findings in ataxia-telangiectasia?
- Progressive neuronal loss— normal at birth, ataxia begins ~2 years old, later in some patients, wheelchair-bound ~10 years old.
- Oculomotor apraxia, dysarthria, and choreoathetosis
- Telangiectasia (appears years after ataxia)
- Sterility
- Risk of leukemia or lymphoma
- Immune deficiency— sinopulmonary infections
What are the lab findings in ataxia-telangiectasia?
- Naïve T-lymphocyte (CD45RA) lymphopenia; poor mitogen responses
- Can have hypogammaglobulinemi a and poor response to immunizations;
- IgA deficiency (80%)
- Elevated AFP and decrease CSA (colony survival assay) to assess radiosensitivity
What is the defect in ataxia-telangiectasia? Is it radiosensitive? Why?
Classswitching recombination defect
ATM is PI3 kinase, responsible for repair in DNA ds breaks; as a result, patients radiosensitive
What is the therapy for ataxia-telangiectasia?
Treatment and prophylactic antibiotics, IVIG, and chemotherapy
Avoid radiation from imaging
Which immunodeficiencies are associated with defects in the AIRE gene?
Chronic mucocutaneous candidiasis (CMC);
Autoimmune polyglandular syndrome (APS-1);
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED)
Are defects in the AIRE gene inherited or mutated?
autosomal recessive
What are the infections or clinical manifestations of defects in the AIRE gene?
Chronic mucocutaneous candidiasis (CMC): Recurrent noninvasive thrush, candidal dermatitis, dystrophic nails, enamel hypoplasia
Autoimmune polyglandular syndrome (APS-1); Endocrinopathies:
Hypoparathyroid (most common)
Autoimmune polyendocrinopathycandidiasisectodermal dystrophy (APECED): Hypoadrenalism, pernicious anemia, DM, vitiligo, alopecia, and hepatitis
What are the lab findings in diseases caused by defects in the AIRE gene?
↓ T proliferation to mitogens and recall antigens
Some IgA deficiency
What is the treatment for diseases caused by defects in the AIRE gene?
Antifungal;
Treat autoimmune disease
What is the inheritance or mutation in CD40L deficiency (HIGM1, hyper-IgM type 1)?
X linked CD40L/CD154 mutation (TNFS5)
What are the infections or clinical findings in CD40L deficiency?
Opportunistic infection, fungal, bacterial, and viral;
Autoimmune hemolytic anemia and neutropenia
What are the lab values in CD40L deficiency?
↓ IgG, IgA, and IgE, levels. Variable high/normal IgM;
Neutropenia
Absent germinal centers
What is the defect in CD40L deficiency?
Ig class switch recombination deficiencies from defect in CD40-CD40L interaction
What is the treatment of CD40L deficiency?
IVIG, PCP prophylaxis GCSF, and HSCT
What is the mutation or inheritance of CD40 deficiency?
AR
CD40 absent
What is CD40 deficiency called?
HIGM3, hyper-IgM type3
What are the infections or clinical findings in CD40 deficiency?
Opportunistic infection, fungal, bacterial, and viral; Autoimmune hemolytic anemia and neutropenia
What are the lab values in CD40 deficiency?
↓ IgG, IgA, and IgE, levels. Variable high/normal IgM;
Neutropenia
Absent germinal centers
What is the defect in CD40 deficiency?
Ig class switch recombination deficiencies from defect in CD40-CD40L interaction
What is the treatment for CD40 deficiency?
IVIG, PCP prophylaxis, and GCSF
What is the inheritance or mutation in DiGeorge’s syndrome?
22q11.2 deletion (~90%)
10p13-14 deletion (Renal/GU defect)
What are the infections or clinical findings in DiGeorge’s syndrome?
- Cellular immune deficiency -> infections. +/- absence of part or all of the thymus
- Hypocalcemia parathyroid deficiency -> tetany/seizures
- Congenital heart disease (tetralogy of Fallot—most common
Type B interrupted aortic arch—2nd common)
Other features: lowset or posteriorly rotated ears, short philtrum, micrognathia, developmental delay, B-cell lymphoma, and autoimmune disease
What are the lab values in DiGeorge’s syndrome?
Complete: naive T cell
What is the mnemonic of DiGeorge’s syndrome?
CATCH 22 (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia, chromosome 22)
What is the therapy of DiGeorge’s syndrome?
Complete DGS: treat like SCID with thymus transplantation and IVIG
Antibiotic prophylaxis— depend on T-cell counts and recall
Live vaccines for patients who have normal T recall
Neuropsychiatric therapy, and surgery of congenital defects
What is the inheritance or mutation of defective NFkB regulation (NEMO NFκB essential modifier)?
X-linked incontinentia pigmenti (Null mutation of NEMO)
X-linked anhydrotic ectodermal dysplasia with immunodeficiency (Hypomorphic mutation in NEMO
LZ-NEMO mutation (X-linked MSMD (Mendelian susceptibility to mycobacterial diseases)
What are the clinical findings or infections in x-linked incontinentia pigmenti (Null mutation of NEMO)?
Lethal in utero (male)
Scarring, alopecia, and hypodontia (female)
What are the lab values in NEMO?
Hypogammaglobuline mia and poor antibody response to polysaccharide
TLR defect (NFκB is central in TLR activation)
Can have decreased NK cytotoxicity
Normal T cell-count and function
What are the defects in NEMO?
Ectodysplasin A receptor cannot induce activation of NFκB +
Defect in CD40 activation pathway
What is the treatment for NEMO?
IVIG and IFNγ
HSCT: under investigation—prior attempts resulted in engraftment difficulties and post transplant complications
What are the infections or clinical findings in X-linked anhydrotic ectodermal dysplasia with immunodeficiency (hypomorphic mutation in NEMO)?
Male—reduced sweat, hyperthermia, hypotrichosis, and hypodontia, conical incisors, nail abnormality
Severe bacterial infections but poor inflammatory responses, opportunistic infections including mycobacteria
Female—usually normal
What are the infections or clinical findings in LZ_NEMO mutation (X-linked MSMD)?
Normal ectoderm; Mycobacterium avium intracellulare is cause of infection.
Disseminated BCG.
What is the defect in LZ-NEMO mutation (X-linked MSMD)?
Impaired production of IL-12 and IFNγ in response to CD40L.
What is the therapy for LZ-NEMO?
Mycobacteria should be typified and treated
Antimycobacteri al prophylaxis in some patients
What are the infections or clinical findings in the immune deficiency predominant NEMO?
Normal ectoderm;
Infections: bacteria, viral, and opportunistic
What are lab findings in the immune deficiency predominant NEMO?
HIGM1/3 phenotype (combined immune defect)
What is the defect in the immune deficiency predominant NEMO?
Defect in class switch recombination due to altered CD40 signaling
What are the different genes affected in Hyper IgE syndromes (HIES, Job’s syndrome)?
AD-STAT-d
AR-DOCK8
AR-Tyk2
What is the treatment for hyper IgE syndromes?
Prophylactic antibiotics (covering staph) and antifungal
IVIG in case of poor antibody response
What is are the infections or clinical findings in AD-STAT-3 hyper IgE?
Recurrent Infections: abscesses, mucocutaneous candidiasis
Pneumonia with pneumatoceles
Severe eczema and eosinophilic pustular folliculitis
Characteristic facies: coarse features, prominent mandible, hypertelorism, and broad nose Skeletal abnormalities: retained primary dentition and scoliosis
Connective tissue disease: hyperextensibility and aortic aneurysms
What are the lab values in AD-STAT-3 Hyper IgE?
IgE > 2000 IU/mL; Eosinophilia
Normal IgM Th17 levels decreased
What are is the triad present in hyper IgE deficiencies? What is the characteristic infection profile? What are the secondary infections?
Triad of: recurrent skin and lung infections, severe eczema, and elevated IgE
Has characteristic infection profile: Staphylococcus aureus, Streptococcus pneumonia, Haemophilus influenzae, and Candida;
Secondary infection by: Pseudomonas aeruginosa and Aspergillus sp
What are the infections or clinical findings in AR-DOCK8 hyper IgE?
Viral skin infections severe difficult to treat: HPV, HSV, VZV, molluscum
Mucocutaneous candidiasis Eczema and allergies
Risks of malignancies Pneumonias but no pneumatoceles
What are the lab values in AR-DOCK8 and AR-Tyk 2 hyper IgE?
Low IgM
More prominent eosinophilia
Lymphopenia
What are the infections or clinical findings in AR-Tyk2?
Same as DOCK8 + disseminated BCG Vasculitis
What pathway is Tyk2 involved in?
Tyk-2 involves in Il-12 signaling pathway to produce IFN-γ
What is the inheritance or mutation of immune dysregulation, polyendrocrinopathy, enteropathy, and X-linked inheritance (IPEX)?
X-linked recessive FOXP3 mutation (not found in every case.)
What are the infections in IPEX?
Severe diarrhea and FTT (enteropathy)
Early-onset type 1 DM thyroid disease, autoimmune cytopenia
Variable skin lesions: erythroderma, exfoliative dermatitis, eczema, psoriasis-like
Severe infections
Coronary artery disease
What are the lab values in IPEX?
Villous atrophy with lymphocytic infiltrates in small bowel
Autoimmune antibodies
Cytopenia
Eosinophilia
High IgE, normal IgG (↓enteropathy), IgM
Normal B/T number and function exp. no Treg
Why does FOXP3 mutation cause autoimmunity?
FOXP3 codes protein involved in Treg (CD4+CD25+) cell development Impair Treg autoimmune
What is the therapy for IPEX?
IVIG
Rx autoimmune and endocrine disease
HSCT
Parenteral nutrition
What is the inheritance or mutation in X-linked lymphoproliferative disease (XLP-1)?
XLP-1: mutation in SH2D1A gene encodes SAP (SLAM-associated protein)
What are the infections/clinical findings in XLP-1?
- Fulminant EBV mononucleosis
- Dysgammaglobulinemia— combined immunodeficiency with severe infections
- Lymphoma: B cell/Burkitt’s, splenomegaly
What are the lab values in XLP?
HLH on BM biopsy
Low IgG, high IgM
↓ CD4 but high CD8. Impair T-cell function.
↓ NK cell number and function
Absent NKT cell
Anemia
How does XLP-1 lead to HLH?
Failure to eliminate EBVinfected B cells -> prolonged Ag presentation + hyperactivation of CTL and macrophages -> HLH
What is the therapy for XLP-1?
IVIG, HSCT, and chemo-therapy
What is the inheritance or mutation for XLP-2?
XLP-2: XIAP ( X-linked inhibitor of apoptosis).
What is the infection or clinical findings of XLP-2?
XLP-2: Colitis, predisposition to hemophagocytic lymphohistiocytosis
What do cells in XLP-2 have increased susceptibility to?
XLP-2: increased susceptibility to apoptotic stimuli
What is the inheritance or mutation of Wiskott-Aldrich syndrome?
WASp X-linked
What is the clinical triad in Wiskott-aldrich syndrome? What are these patients at increased risk for?
- Thrombocytopenia + bleeding diathesis,
- eczema,
- recurrent infections.
Risk for: autoimmunity and malignancy (EBVrelated lymphoma)
What are the lab values in Wiskott-Aldrich Syndrome?
↑ IgE, IgA;
↓ IgM; and
Normal IgG but impaired Ab responses.
Impair T-cell proliferation
↓ Platelet size
↓ Platelet function
What are two mnemonics for Wiskott-Aldrich syndrome?
PET WASP:
pyogenic infection, eczema, thrombocytopenia, and WASp mutation
HOT ITCH THROM;
Wiskott-hot Aldrich-itch Syndrome Thrombocytopenia
What is the treatment for Wiskott-Aldrich syndrome?
HSCT treatment of choice Treatment of infections, IVIG, and splenectomy
What mutation causes APECED and what is the most common endocrinopathy seen in the disease?
AIRE mutation, hypoparathyroidism
What mutation causes IPEX and what cell is affected by the disease?
FOXP3 mutation, Treg cell
