Primary Immunodeficiencies Flashcards
List warning signs of primary immunodeficiency
4+ ear infections in a year 2+ sinus infections in a year 2 months of antibiotics without effect 2+ pneumonias per year Failure to thrive Recurrent deep abscesses Persistent thrush or fungal infection Need for IV antibiotics to clear infections Two or more deep infections incl septicemia Family history of PI
List signs of B cell deficiency
Recurrent sinopulmonary infections or sepsis
Infections with encapsulated organisms
Chronic enteroviral meningoencephalitis
What lab tests are used to work up B cell deficiencies
Ig levels
Specific antibody titers
Flow cytometry
What disease states present with B cell deficiencies?
X linked agammaglobulinemia
Common variable immunodeficiency
Selective IgA deficiency
List signs of T cell deficiency
Opportunistic infections
Recurrent and severe common infections
Failure to thrive
List lab tests used to work up T cell deficiencies
CBC with differential
Flow cytometry
T cell functional study
Ig levels
List disease states associated with T cell deficiency
DiGeorge syndrome
Wiskott Aldrich syndrome
SCID (B and T cell)
CID
List signs of phagocyte deficiency
Soft tissue abscess or lymphadenitis
Infection with catalase + organisms (staph, serratia, aspergillus)
Poor wound healing
List lab test used to work up phagocyte deficiency
CBC with differential
Neutorphil oxidative burst assay
Flow cytometry for adhesion molecules
List disease states associated with phagocyte deficiency
Chronic granulomatous disease
Leukocyte adhesion defecit
List signs of complement deficiency
Recurrent disseminated Neisseria infection
Autoimmune disease
Bacterial sepsis
List lab tests used to work up complement deficiency
CH50 measures entire complement cascade
AH50
List disease states associated with complement deficiency
Classical complement deficiency
Alternative complement defect
List presenting signs of innate immune defects
Septicemia
Poor inflammatory response
List lab tests used to work up innate immune defects
TLR signaling
List disease states associated with innate immune defects
IRAK 4 mutation
NEMO mutation
MyD88 mutation
The majority of primary immune deficiencies are due to deficiency in ______
antibodies
#2: combined cellular and antibody #3: phagocytic #4: cellular #5: complement
Describe the rationale for SCID screening on the newborn screening panel
- many genotypes, many mutations
- diagnosis often not apparent on exam
- treatable but life threatening
- early treatment associated with better outcomes
- cost effective
T cell recombination in the thymus creates ______ as a byproduct. They are stable and can be detected by PCR in newly formed T cells but are diluted out as T cells undergo successive division
TRECs- TCRa rearrangement excision circles
Newborn screening for SCID involves quantitative PCR to determine the number of ______ present and is confirmed with ______
TRECs
Flow cytometry
What findings will be present on flow cytometry of a child with SCID?
Low absolute lymphocytes
Low CD3
Low CD19
Normal NK cells
How is SCID treated?
immune reconstitution: bone marrow transplant, gene therapy, PEG-ADA, thymic transplant
What is the classic triad of DiGeorge syndrome?
Conotruncal cardiac anomaly
Hypoplastic thymus
Hypocalcemia
Describe the pathophysiology of DiGeorge syndrome
Deletions in chromosomes 22 (or 10)
teratogens that presumably inhibit neural crest cell migration at critical times during development result in chromosomal defects. Examples: accutane, EtOH, maternal diabetes.
How can DiGeorge syndrome be diagnosed?
FISH
How can DiGeorge syndrome be treated?
Immunologic monitoring
Guidance re: live vaccines
Thymic transplantation if complete syndrome
_______ is the most common humoral immune deficiency but is poorly understood at the molecular level.
Common variable immunodeficiency
What is the main defect in CVID?
Primarily a defect in B cell differentiation or function
Also often involves autoimmunity
What age is most commonly affected by CVID?
Bimodal age of onset- first and third decades of life
Lis three diagnostic criteria for CVID
Male or female with marked decrease in IgG, IgM, IgA PLUS
1. Onset greater than 2 years of age
2 .Absence of isohemagglutinins or poor response to vaccines
3. Defined causes of hypogammaglobulinemia have been excluded
There is increased incidence of _____, _____, and ___ in CVID
lymphoid malignancy, autoimmune disease, atopy
List some autoimmune manifestations of CVID
Hematologic: autoimmune cytopenias GI: pernicious anemia,celiac, IBD Rheumatologic: SLE, RA, JRA, vasculitis Endocrine: Hashimoto’s, Type 1 DM Dermatologic: vitiligo, alopecia Neurologic: Guillain-Barre
What treatments are used for CVID?
Gammaglobuline therapy
Aggressive antibiotics for bacterial infections
Immunosuppression ofr autoimmunity
BMT????
Wiskott Aldrich Syndrome shows ________ inheritance and typically presents with recurrent infections, thrombocytopenia, and eczema
X linked
What is the normal role of the Wiskott Aldrich protein
actin cytoskeleton modulation
Describe lab findings in WAS
Low platelets with low volume
Lymphopenia
Increased IgA, IgE and normal- low IgM and IgG
List treatments of WAS
- possible prophylactic antibiotics against PCP
- acyclovir to prevent HSV
- gammaglobulin replacement therapy
- curative options: HSCT, gene therapy trials underway
_________ is a primary immune deficiency characterized by severe immune dysregulation after EBV infection.
X linked lymphoproliferative disorder, XLP
Describe the clinical phenotype of XLP
fatal mononucleosis, hemophagocytic lymphohistiocytosis, lymphoma, aplastic anemia
What is the genetic defect in XLP?
Genetic mutation in SH2D1A gene which encodes intracellular signaling protein, SLAM associated protein. SAP is necessary for NK cell development, CD8 response to EBV
How is XLP treated?
Bone marrow transplant
B cell depletion early in EBV infection course
Chronic granulomatous disease shows _____ inheritance and involves disruption of NADPH oxidase complex formation
X linked
What are the clinical manifestations of chronic granulomatous disease?
Recurrent abscess, pneumonia, osteomyelitis, gingivitis, poor wound healing, colitis, GI obstruction.
Susceptibility to catalase positive organisms
How is chronic granulomatous disease treated
Antibacterial and antifungal prophylaxis Interferon gamma prophylaxis Steroid therapy for dysregulated inflammatory responses Bone marrow transplant Gene therapy
Summarize the genetics of the diseases presented in lecture
X linked: WAS, XLP, CGD
SDID: various, can be X linked, AR, mitochondrial
DiGeorge: chromosomal deletion
CVID:
