Primary Immunodeficiency Flashcards
When a patient has an ID (immunodeficiency), they are more likely to develop…
Lymphomas or Autoimmune diseases
B Cell Defect
When will it first manifest?
3-6 months after birth (before then, the child is protected by Mom’s antibodies)
B Cell Defect
Clinical Manifestations
Recurrent sino-pulmonary infections and septicemias caused by infection with extracellular pyogenic bacteria
B Cell Defect
What is the pt more likely to get infected with?
Encapsulated bacteria
Strep, Staph, Haemophilus
Also susceptible to systemic and atypical CNS disease with enteroviruses normally found in GI tract
T Cell Defect
When will it first manifest?
At birth
T Cell Defect
Clinical Manifestations and Likely infections
Infections that require T cell/macrophage interaction
Listeria, Mtb, Toxoplasmosis, fungi, protozoa Most viruses (from CD8 lack)
A B and T cell defect is known as…
Severe Combined Immunodeficiency (SCID)
When would a baby with SCID first get sick?
At birth
What is the general difference in the kinds of recurrent infections found in B cell defects vs. T cell defects?
B cell defects
Mostly Bacterial
T Cell defects
May include viral, fungal, opportunistic infections too
In general, how would you test whether a patient has a B cell defect?
Measure serum immunoglobulin
Do a serum protein electrophoresis
In general, how would you test whether a patient has a T cell defect?
Do a blood count with CBC –> do they have lymphocytes?
Could also measure whether they mount a positive skin test to common antigens (like Candida or Histoplasmosis)
What surgical procedure must be done with extreme care in people with immunodeficiencies? Why?
Lymph node biopsy
Very easy to get an infection with a sloppy surgeon
What is the only truly pure B cell defect?
X linked agammaglobulinemia
X linked agammaglobulinemia
Where is the mutation?
BLK Receptor, a signaling tyrosine receptor needed for growth and development of B cells
X linked agammaglobulinemia
What is the basic pathological problem?
The patient has no normal B cells anywhere, so they have almost no antibody present in circulation!
X linked agammaglobulinemia
Treatment
IVIG
Hyper IgM Syndrome
Where is the mutation?
CD40L, a receptor on T cells
Hyper IgM Syndrome
What is the pathogenesis?
Mutation of CD40L prevents isotype switch from occurring
Inability of T cells to be activated and provide cytokines for isotype switch
No isotype switch –> log IgG, low IgA, high IgM
Hyper IgM Syndrome
Treatment
Sten Cell Transplant
Selective IgA Deficiency
What is the pathogenesis?
IgG and IgM levels are normal, but IgA levels are decreased/absent.
No increased infections because IgG and IgM simply substitute for IgA
Selective IgA Deficiency
What is the major concern with these patients?
These patients may develop IgG anti-IgA antibodies.
If they need a blood transfusion, there will likely be residual IgA on the donor RBCs and the patient will mount an immune response. Could cause anaphylaxis and death in IgA deficient patients
EBV X linked agammaglobulinemia
What is the mutation and how does it become activated?
Mutation in signaling receptor of CD8 cells, which becomes activated by EBV infection of B cells
EBV X linked agammaglobulinemia
Pathogenesis
The mutation in the CD8 receptor renders the CD8 cell unstoppably active, causing the T cells to kill any lymphocyte they see.
Causes global immune dysfunction and death
Common Variable Immunodeficiency (CVID)
What is the fundamental defect?
Inability of a B cell to differentiate to a plasma cell
Common Variable Immunodeficiency (CVID)
When does CVID present?
Symptoms can begin anytime after 2 years of age (infancy is usually normal)
Common Variable Immunodeficiency (CVID)
What is seen on lab tests?
Decreased IgM, IgG, and IgA levels
Normal amount of B cells in the periphery
Common Variable Immunodeficiency (CVID)
What does it commonly culminate in?
Lymphoma
Common Variable Immunodeficiency (CVID)
What would be seen in a lymph biopsy?
Total lack of germinal centers
Common Variable Immunodeficiency (CVID)
Pathogenesis
Nobody really knows
Common Variable Immunodeficiency (CVID)
Treatment
IVIG will work until T cell defects become prominent
Then, HSC transplants can be successful
Common Variable Immunodeficiency (CVID)
Describe the disease progression
Decreased IgG, IgM, and IgA in early stages due to inability of B cell to mature into a plasma cell.
Progresses to overt T cell symptoms and multiple autoimmune diseases
Common Variable Immunodeficiency (CVID)
What should you always be monitoring for?
Lymphomas!
Thymic Aplasia
What is the mutation?
22.q.11.2 deletion
Thymic Aplasia
When does the baby first get sick?
Sick from birth with fungal infections because they have no thymus
Thymic Aplasia
Often arises with structural mutations in the 3rd/4th pharyngeal pouches in embryological development. What does this cause?
Thymic aplasia always presents with either Tetralogy of Fallot or Pulmonary Stenosis.
Thymic Aplasia
Symptoms
Tetralogy of Fallot or Pulmonary Stenosis Facial dysmorphism Deficient parathyroid glands Symptomatic hypocalcemia Lymphopenia Decreased lymph tissue
SCID
Where are common sites for mutation?
JAK3
ADA
Rag 1 and 2
SCID
What test may be done to determine if T cells are being made?
TREC analysis (Remember: TRECs are formed during the rearrangement of the TCR)
TRECs can be detected with PCR
If TRECs are present, the thymus is present and is making T cells
Wiskott-Aldrich Syndrome
Symptoms
Eczema
Thrombocytopenia
Recurrent bleeding episodes
Cannot make antibody against polysaccharides
Wiskott-Aldrich Syndrome
What is the pathological defect?
Moderate T cell deficiency
Ataxia Telangiectasia
What is the pathological defect?
Loss of function of DNA repair
High sensitivity to radiation
Ataxia Telangiectasia
Symptoms
Early Cerebellar Dysfunction
Recurrent infections of all kinds
High sensitivity to radiation
High risk of lymphoma
Bare Lymphocyte Syndrome
What is the pathological defect?
Defect in formation and transport of MHC I and II complexes to the cell membrane
If you can’t present MHC Class I, you’ll do poorly with what kind of infections?
Viral
If you can’t present MHC Class II, you’ll do poorly with what kind of infections?
Tuberculosis
Job (Hyper IgE) Syndrome
Symptoms
Hugely high IgE levels Eczema Recurrent T and B cell infections High IL4 and IL13 Th17 abnormalities
Chediak Higashi Syndrome
What would you see on blood smear?
Strange looking neutrophils with huge blue granules
Chediak Higashi Syndrome
Symptoms
Pyogenic infections with bleeding tendency
Recurrent infections, but normal T and B cells
Chronic Granulomatous Disease
Inheritance
X linked recessive
Chronic Granulomatous Disease
Where is the mutation and how does this affect the patient?
Mutation in the NADPH respiratory burst system
Neutrophils can phagocytize but cannot kill because they cannot generate sufficient H2O2
Chronic Granulomatous Disease
What infections are common?
Catalase + organisms (Staph, fungi)
Chronic Granulomatous Disease
Treatment
IFN-y effective in some
Future candidate for gene transfer
A deficiency in late complement components C5-C9 predisposes a patient to…
Neisserial infections
TLR-MyD88 deficiency predisposes to…
Pyogenic infections
CLR-Mannose binding lectin deficiency predisposes to…
Bacterial and fungal infections
NLR-NLRP3 deficiency leads to…
Dysregulation of IL-1 and autoinflammatory syndromes
