Immunodeficiencies Resident Education Lecture Series

Factoids to start Acquired are more common Acquired are more common IatrogenicIatrogenic AIDSAIDS Genetic: over 95 different diseases Genetic: over 95 different diseases B cell most common (IgA def is #1)B cell most common (IgA def is #1) T cellsT cells PhagocytesPhagocytes ComplementComplement

How to start Screen them all for HIV Screen them all for HIV Infections: #, site, bug, type, etc. Infections: #, site, bug, type, etc. Daycare Daycare 2 serious bacterial infections at the same site: think anatomic 2 serious bacterial infections at the same site: think anatomic Constant URI without fever: think allergies Constant URI without fever: think allergies 2 isolated bacteremia/meningitis: think complement or antibody defects 2 isolated bacteremia/meningitis: think complement or antibody defects

From the CBC Normal Absolute Lymphocyte Count (ALC): Normal Absolute Lymphocyte Count (ALC): excludes T cell defects, AIDSexcludes T cell defects, AIDS excludes congenital and acquired neutropenias and LAD (increased ANC)excludes congenital and acquired neutropenias and LAD (increased ANC) Normal platelets: Normal platelets: excludes Wiscott Aldrich Syndrome (WAS)excludes Wiscott Aldrich Syndrome (WAS) No Howell-Jolly bodies: no asplenia No Howell-Jolly bodies: no asplenia

Screening for B cell defects IgA: most common IgA: most common IgG and IgM: agammaglobulinemia IgG and IgM: agammaglobulinemia Isohemaglutinins: Isohemaglutinins: IgM to blood group(s): get if Ig’s are low to see if production failure vs. lossIgM to blood group(s): get if Ig’s are low to see if production failure vs. loss Antibody titers to immunizations Antibody titers to immunizations AGE NORM’S: IgG and A are not at adult levels until age 7 AGE NORM’S: IgG and A are not at adult levels until age 7 Check flow: if no B cells, usually = Bruton Check flow: if no B cells, usually = Bruton

IgG subclasses No good age norm’s No good age norm’s Lows can be transient Lows can be transient Poorly correlated with disease Poorly correlated with disease BUT, can be a harbinger of CVID BUT, can be a harbinger of CVID Best test: immunize with protein then polysaccharide vaccines; check serum before and after. If they respond, they’re okay. Best test: immunize with protein then polysaccharide vaccines; check serum before and after. If they respond, they’re okay.

T cell defects Mucocutaneous candida, chronic diarrhea, PCP, FTT, disseminated CMV/VZV/HSV Mucocutaneous candida, chronic diarrhea, PCP, FTT, disseminated CMV/VZV/HSV Examples: SCID, CVID, AIDS Examples: SCID, CVID, AIDS ALC usually low, though can be normal in DiGeorge ALC usually low, though can be normal in DiGeorge (NOTE: Adult ALC > 1000; NB ALC > 4000)(NOTE: Adult ALC > 1000; NB ALC > 4000) Candida skin test: kids should respond by age 9 mos; a normal response virtually rules out T cell problems. Candida skin test: kids should respond by age 9 mos; a normal response virtually rules out T cell problems. Can also check flow, do mitogen/antigen stim, assay cytokines Can also check flow, do mitogen/antigen stim, assay cytokines

Phagocytic cell defects Skin infections without underlying skin disease Skin infections without underlying skin disease Abscesses of skin, liver, lung, nodes Abscesses of skin, liver, lung, nodes Examples: CGD, LAD Examples: CGD, LAD Check flow (NK cells, CD11/CD18 [LAD-1], CD15 [LAD-2, aka Sialyl Lewis X – VERY rare) Check flow (NK cells, CD11/CD18 [LAD-1], CD15 [LAD-2, aka Sialyl Lewis X – VERY rare)

Complement problems CH50 assay is the screen; need all the other levels to be normal for it to be normal CH50 assay is the screen; need all the other levels to be normal for it to be normal Complement spontaneously activates Complement spontaneously activates blood that has been sitting around is inappropriate for testingblood that has been sitting around is inappropriate for testing CH50 levels should turn up VERY low – like 11 CH50 levels should turn up VERY low – like 11

Gene Markers for: X-linked SCID X-linked SCID XL IgA XL IgA XL Hyper IgM XL Hyper IgM There is also specific testing for CGD There is also specific testing for CGD

(Selective) IgA deficiency (Selective) IgA deficiency Most common: 1 in 500? Most common: 1 in 500? Related to CVID – can run in sibs Related to CVID – can run in sibs Can evolve to normal or become increasingly deficient over years Can evolve to normal or become increasingly deficient over years Have B cells, but they don’t go on to form plasma cells. Have B cells, but they don’t go on to form plasma cells. Allergy-type sxs and chronic mucosal infx Allergy-type sxs and chronic mucosal infx

CVID Wastebasket dx for B cell + Ig deficient pt’s Wastebasket dx for B cell + Ig deficient pt’s Some have decreased total B cells, some decreased T-helpers, some increased T-suppressors. Some have decreased total B cells, some decreased T-helpers, some increased T-suppressors. Low Ig’s in any combination that includes “G.” (G, G+A, G+A+M) Low Ig’s in any combination that includes “G.” (G, G+A, G+A+M) Recurrent bacterial infections; Recurrent bacterial infections; onset in infancy, at puberty, or even later.onset in infancy, at puberty, or even later. Ears, nose, sinuses, bronchi, lungs.Ears, nose, sinuses, bronchi, lungs. Can have chronic lung dz.Can have chronic lung dz. Enlarged neck and chest LN’s; can have increased incidence of mycoplasma and/or chlamydia Enlarged neck and chest LN’s; can have increased incidence of mycoplasma and/or chlamydia

Chronic Granulomatous Disease Short arm of the X chromosome Short arm of the X chromosome NBT (nitro blue tetrazoleum): NBT (nitro blue tetrazoleum): feed to PMN’s with a particle (bacteria, latex). If the hexose monophosphate path is nl, the dye is reduced (turns purple). Heparin interferes. High false (-) rate.feed to PMN’s with a particle (bacteria, latex). If the hexose monophosphate path is nl, the dye is reduced (turns purple). Heparin interferes. High false (-) rate. Respiratory burst assay: Respiratory burst assay: non-fluorescing dye to PMN’s; addition of particle makes it fluoresce. A quantitative test – can pick up carriers.non-fluorescing dye to PMN’s; addition of particle makes it fluoresce. A quantitative test – can pick up carriers. Poor phagocytosis; poor peroxidase production Poor phagocytosis; poor peroxidase production Infections with non-peroxidase-producing org’s: staph, serratia Infections with non-peroxidase-producing org’s: staph, serratia Abscesses of lung, LN; also infx of skin, liver, bone Abscesses of lung, LN; also infx of skin, liver, bone

Bruton’s (XL) gammaglobulinemia Recurrent pyogenic infections from infancy/early childhood: mucous membranes. Recurrent pyogenic infections from infancy/early childhood: mucous membranes. Ears, sinuses, lungs, GI tract, bacteremias; also increased viral infections. Ears, sinuses, lungs, GI tract, bacteremias; also increased viral infections. Family history of affected lateral (maternal) male relatives Family history of affected lateral (maternal) male relatives No tonsils or palpable lymph nodes (they have nodes, but no B cell centers, so non-palpable.) No tonsils or palpable lymph nodes (they have nodes, but no B cell centers, so non-palpable.) Few mature B cells (unlike CVID) [Have pre-B’s] Few mature B cells (unlike CVID) [Have pre-B’s]

XL Agammaglob, cont. Mutation in B cell specific protein (a tyrosine kinase – “BTK”) in the proto-oncogenic src family (X q 22): abnormal kinase activity in B and pre-B Mutation in B cell specific protein (a tyrosine kinase – “BTK”) in the proto-oncogenic src family (X q 22): abnormal kinase activity in B and pre-B Over 300 different mutations in BTK can result in this disease phenotype. Over 300 different mutations in BTK can result in this disease phenotype. The most typical form has a mutation in the area of the protein for catalytic function.The most typical form has a mutation in the area of the protein for catalytic function. Atypical forms have protein-protein interaction problems and are more subtle clinically.Atypical forms have protein-protein interaction problems and are more subtle clinically. Mouse model XID: N-terminal mutation (function unknown)Mouse model XID: N-terminal mutation (function unknown)

B cell (-) [AR] Agammaglob’s μ heavy chain gene mutation μ heavy chain gene mutation λ 5/14.1 (surrogate light chain) mutation λ 5/14.1 (surrogate light chain) mutation Ig α (B cell α Ag receptor) mutation Ig α (B cell α Ag receptor) mutation B cell linker protein (BLNK) mutation B cell linker protein (BLNK) mutation

XL HyperIgM in vivo, no IgG, A, or E in vivo, no IgG, A, or E Can have the “no tonsils, no LN’s” presentation Can have the “no tonsils, no LN’s” presentation B cells can make IgE with IL-4 and anti-CD40 in vitro B cells can make IgE with IL-4 and anti-CD40 in vitro Gene mutation at CD40L (it can’t “hear from” the T cell) Gene mutation at CD40L (it can’t “hear from” the T cell) See also AR form See also AR form

AR HyperIgM Normal # and phenotype of B and T cells Normal # and phenotype of B and T cells Still can’t isotype switch (like XL) Still can’t isotype switch (like XL) But, they DO make B cell centers (tonsils, LN’s) But, they DO make B cell centers (tonsils, LN’s) Mutation on 12p13 for AID: make IgM, have cytokines, but lack RAG enzyme for Ag linking; can’t get from primary to secondary repertoire. Mutation on 12p13 for AID: make IgM, have cytokines, but lack RAG enzyme for Ag linking; can’t get from primary to secondary repertoire.

NEMO deficiency (I am not making this up) Nuclear factor κβ Essential MOdulator Nuclear factor κβ Essential MOdulator Anhydrotic eczema, incontinentia pigmenta, osteopetrosis, other depending on where in codon-land the mutation occurs. Anhydrotic eczema, incontinentia pigmenta, osteopetrosis, other depending on where in codon-land the mutation occurs. Some have a phenotype like hyperIgM Some have a phenotype like hyperIgM

Wiskott Aldrich Eczema, thrombocytopenia; infections of ears, lungs, meninges. Opportunistic infections and bugs with capsular polysaccharide Ag’s Eczema, thrombocytopenia; infections of ears, lungs, meninges. Opportunistic infections and bugs with capsular polysaccharide Ag’s Poor response to polysaccharide antigens but normal IgG 2 Poor response to polysaccharide antigens but normal IgG 2 (So look for Ab’s, not IgG subclasses) Xp Xp WASP gene binds lots of signaling molecules WASP gene binds lots of signaling molecules

XL Lymphoproliferative Dz T and B cell T and B cell SLAM-SAP interaction (costimulatory signaling) problems SLAM-SAP interaction (costimulatory signaling) problems

Hyper IgE Abscesses (staph), esp skin (boils) but also lung Abscesses (staph), esp skin (boils) but also lung Lung abscesses progressing to giant cysts/pneumatocoeles. Lung abscesses progressing to giant cysts/pneumatocoeles. No diagnostic test; markedly elevated levels of IgE are even seen in atopic dermatitis No diagnostic test; markedly elevated levels of IgE are even seen in atopic dermatitis

DiGeorge Associated abnormalities of face, brain, thymus, parathyroid, heart/aorta (and platelets!) Associated abnormalities of face, brain, thymus, parathyroid, heart/aorta (and platelets!) FISH for 11q22 FISH for 11q22 Hypocalcemia, seizures Hypocalcemia, seizures Extremely variable phenotype Extremely variable phenotype

SCID Stem cells defective or absent Stem cells defective or absent OR T helpers defective or absent OR T helpers defective or absent OR thymus defective or absent (no T cell maturation OR thymus defective or absent (no T cell maturation B cells are affected because there’s no T help B cells are affected because there’s no T help ADA def: no T or B cells ADA def: no T or B cells PNP (purine nucleoside phosphorolase): much more T cell PNP (purine nucleoside phosphorolase): much more T cell Invasive infections and really serious viral infections; PCP Invasive infections and really serious viral infections; PCP

Ataxia-Telangiectasia T and B cells; usually have abnormal Ig’s (A or E; some G) T and B cells; usually have abnormal Ig’s (A or E; some G) Ataxic first, then develop telangiectasia, especially of eye Ataxic first, then develop telangiectasia, especially of eye Infections of lungs, sinuses; with bacteria and viruses Infections of lungs, sinuses; with bacteria and viruses Increased AFP level Increased AFP level

From ABP Certifying Exam Content Outline Immunologic problems Presenting signs and symptoms of a potentially immunodeficient child Recognize clinical characteristics of antibody deficiency syndromes after 4 to 6 months of age (severe first infections and/or chronic and recurrent infections in more than one anatomic site) Recognize clinical characteristics of immunodeficiency present in the first few months after birth (failure to thrive, chronic diarrhea, overwhelming infections with viral, bacterial, and/or opportunistic infections) Screening tests Plan the laboratory evaluation of antibody function (quantitative immunoglobulin concentrations, specific antibody to Hemophilus influenzae, pneumococcus, tetanus, rubeola, rubella) Plan the laboratory evaluation of cell-mediated immunity (lymphocyte counts; delayed type skin tests to Candida, tetanus, and Trichophyton) Treatment

Credits Meghen Browning MD Meghen Browning MD