ImmunodeficienciesImmunodeficiencies

Resident Education Resident Education Lecture SeriesLecture Series

Factoids to startFactoids to start

Acquired are more common Acquired are more common • IatrogenicIatrogenic• AIDSAIDS

Genetic: over 95 different diseasesGenetic: 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 startHow to start

Screen them all for HIVScreen them all for HIV Infections: #, site, bug, type, etc.Infections: #, site, bug, type, etc. DaycareDaycare 2 serious bacterial infections at the same 2 serious bacterial infections at the same

site: think anatomicsite: think anatomic Constant URI without fever: think allergiesConstant URI without fever: think allergies 2 isolated bacteremia/meningitis: think 2 isolated bacteremia/meningitis: think

complement or antibody defectscomplement or antibody defects

From the CBCFrom 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 excludes congenital and acquired neutropenias

and LAD (increased ANC)and LAD (increased ANC) Normal platelets: Normal platelets:

• excludes Wiscott Aldrich Syndrome (WAS)excludes Wiscott Aldrich Syndrome (WAS) No Howell-Jolly bodies: no aspleniaNo Howell-Jolly bodies: no asplenia

Screening for B cell defectsScreening for B cell defects

IgA: most commonIgA: most common IgG and IgM: agammaglobulinemiaIgG and IgM: agammaglobulinemia Isohemaglutinins: Isohemaglutinins:

• IgM to blood group(s): get if Ig’s are low to see IgM to blood group(s): get if Ig’s are low to see if production failure vs. lossif production failure vs. loss

Antibody titers to immunizationsAntibody titers to immunizations AGE NORM’S: IgG and A are not at adult AGE NORM’S: IgG and A are not at adult

levels until age 7levels until age 7 Check flow: if no B cells, usually = BrutonCheck flow: if no B cells, usually = Bruton

IgG subclassesIgG subclasses

No good age norm’sNo good age norm’s Lows can be transientLows can be transient Poorly correlated with diseasePoorly correlated with disease BUT, can be a harbinger of CVIDBUT, can be a harbinger of CVID Best test: immunize with protein Best test: immunize with protein

then polysaccharide vaccines; check then polysaccharide vaccines; check serum before and after. If they serum before and after. If they respond, they’re okay.respond, they’re okay.

T cell defectsT cell defects Mucocutaneous candida, chronic diarrhea, Mucocutaneous candida, chronic diarrhea,

PCP, FTT, disseminated CMV/VZV/HSVPCP, FTT, disseminated CMV/VZV/HSV Examples: SCID, CVID, AIDSExamples: SCID, CVID, AIDS ALC usually low, though can be normal in ALC usually low, though can be normal in

DiGeorge DiGeorge • (NOTE: Adult ALC > 1000; NB ALC (NOTE: Adult ALC > 1000; NB ALC >> 4000) 4000)

Candida skin test: kids should respond by Candida skin test: kids should respond by age 9 mos; a normal response virtually age 9 mos; a normal response virtually rules out T cell problems.rules out T cell problems.

Can also check flow, do mitogen/antigen Can also check flow, do mitogen/antigen stim, assay cytokinesstim, assay cytokines

Phagocytic cell defectsPhagocytic cell defects

Skin infections without underlying Skin infections without underlying skin diseaseskin disease

Abscesses of skin, liver, lung, nodesAbscesses of skin, liver, lung, nodes Examples: CGD, LADExamples: CGD, LAD Check flow (NK cells, CD11/CD18 Check flow (NK cells, CD11/CD18

[LAD-1], CD15 [LAD-2, aka Sialyl [LAD-1], CD15 [LAD-2, aka Sialyl Lewis X – VERY rare)Lewis X – VERY rare)

Complement problemsComplement problems

CH50 assay is the screen; need all CH50 assay is the screen; need all the other levels to be normal for it to the other levels to be normal for it to be normalbe normal

Complement spontaneously activatesComplement spontaneously activates• blood that has been sitting around is blood that has been sitting around is

inappropriate for testinginappropriate for testing CH50 levels should turn up VERY low CH50 levels should turn up VERY low

– like 11– like 11

Gene Markers for:Gene Markers for:

X-linked SCIDX-linked SCID XL IgAXL IgA XL Hyper IgMXL Hyper IgM

There is also specific testing for CGDThere 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 sibsRelated to CVID – can run in sibs Can evolve to normal or become Can evolve to normal or become

increasingly deficient over yearsincreasingly deficient over years Have B cells, but they don’t go on to Have B cells, but they don’t go on to

form plasma cells.form plasma cells. Allergy-type sxs and chronic mucosal Allergy-type sxs and chronic mucosal

infxinfx

CVIDCVID

Wastebasket dx for B cell + Ig deficient pt’sWastebasket dx for B cell + Ig deficient pt’s Some have decreased total B cells, Some have decreased total B cells,

some decreased T-helpers, some decreased T-helpers, some increased T-suppressors. some increased T-suppressors.

Low Ig’s in any combination that includes “G.” Low Ig’s in any combination that includes “G.” (G, G+A, G+A+M)(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; Enlarged neck and chest LN’s; can have increased incidence of mycoplasma can have increased incidence of mycoplasma and/or chlamydiaand/or chlamydia

Chronic Granulomatous Chronic Granulomatous DiseaseDisease

Short arm of the X chromosomeShort arm of the X chromosome NBT (nitro blue tetrazoleum): NBT (nitro blue tetrazoleum):

• feed to PMN’s with a particle (bacteria, latex). feed to PMN’s with a particle (bacteria, latex). If the hexose monophosphate path is nl, the dye is If the hexose monophosphate path is nl, the dye is reduced (turns purple). reduced (turns purple). Heparin interferes. High false (-) rate.Heparin interferes. High false (-) rate.

Respiratory burst assay: Respiratory burst assay: • non-fluorescing dye to PMN’s; addition of particle makes non-fluorescing dye to PMN’s; addition of particle makes

it fluoresce. A quantitative test – can pick up carriers.it fluoresce. A quantitative test – can pick up carriers. Poor phagocytosis; poor peroxidase productionPoor phagocytosis; poor peroxidase production Infections with non-peroxidase-producing org’s: Infections with non-peroxidase-producing org’s:

staph, serratiastaph, serratia Abscesses of lung, LN; also infx of skin, liver, Abscesses of lung, LN; also infx of skin, liver,

bonebone

Bruton’s (XL) gammaglobulinemiaBruton’s (XL) gammaglobulinemia

Recurrent pyogenic infections from Recurrent pyogenic infections from infancy/early childhood: mucous membranes. infancy/early childhood: mucous membranes.

Ears, sinuses, lungs, GI tract, bacteremias; also Ears, sinuses, lungs, GI tract, bacteremias; also increased viral infections.increased viral infections.

Family history of affected lateral (maternal) Family history of affected lateral (maternal) male relativesmale relatives

No tonsils or palpable lymph nodes (they have No tonsils or palpable lymph nodes (they have nodes, but no B cell centers, so non-palpable.)nodes, but no B cell centers, so non-palpable.)

Few mature B cells (unlike CVID) Few mature B cells (unlike CVID) [Have pre-B’s][Have pre-B’s]

XL Agammaglob, cont.XL Agammaglob, cont. Mutation in B cell specific protein (a tyrosine Mutation in B cell specific protein (a tyrosine

kinase – “BTK”) in the proto-oncogenic src kinase – “BTK”) in the proto-oncogenic src family (X q 22): abnormal kinase activity in family (X q 22): abnormal kinase activity in B and pre-BB and pre-B

Over 300 different mutations in BTK can Over 300 different mutations in BTK can result in this disease phenotype. result in this disease phenotype. • The most typical form has a mutation in the area The most typical form has a mutation in the area

of the protein for catalytic function. of the protein for catalytic function. • Atypical forms have protein-protein interaction Atypical forms have protein-protein interaction

problems and are more subtle clinically.problems and are more subtle clinically.• Mouse model XID: N-terminal mutation (function Mouse model XID: N-terminal mutation (function

unknown)unknown)

B cell (-) [AR] Agammaglob’sB cell (-) [AR] Agammaglob’s

μ heavy chain gene mutationμ heavy chain gene mutation λ 5/14.1 (surrogate light chain) λ 5/14.1 (surrogate light chain)

mutationmutation Ig α (B cell α Ag receptor) mutationIg α (B cell α Ag receptor) mutation B cell linker protein (BLNK) mutationB cell linker protein (BLNK) mutation

XL HyperIgMXL HyperIgM

in vivoin vivo, no IgG, A, or E, no IgG, A, or E Can have the “no tonsils, no LN’s” Can have the “no tonsils, no LN’s”

presentationpresentation B cells can make IgE with IL-4 and B cells can make IgE with IL-4 and

anti-CD40 anti-CD40 in vitroin vitro Gene mutation at CD40L (it can’t Gene mutation at CD40L (it can’t

“hear from” the T cell)“hear from” the T cell) See also AR formSee also AR form

AR HyperIgMAR HyperIgM

Normal # and phenotype of B and T Normal # and phenotype of B and T cellscells

Still can’t isotype switch (like XL)Still can’t isotype switch (like XL) But, they DO make B cell centers But, they DO make B cell centers

(tonsils, LN’s)(tonsils, LN’s) Mutation on 12p13 for AID: make Mutation on 12p13 for AID: make

IgM, have cytokines, but lack RAG IgM, have cytokines, but lack RAG enzyme for Ag linking; can’t get from enzyme for Ag linking; can’t get from primary to secondary repertoire.primary to secondary repertoire.

NEMO deficiencyNEMO deficiency(I am not making this up)(I am not making this up)

Nuclear factor Nuclear factor κβκβ Essential Essential MOdulatorMOdulator

Anhydrotic eczema, incontinentia Anhydrotic eczema, incontinentia pigmenta, osteopetrosis, other pigmenta, osteopetrosis, other depending on where in codon-land depending on where in codon-land the mutation occurs.the mutation occurs.

Some have a phenotype like Some have a phenotype like hyperIgMhyperIgM

Wiskott AldrichWiskott Aldrich

Eczema, thrombocytopenia; infections of Eczema, thrombocytopenia; infections of ears, lungs, meninges. Opportunistic ears, lungs, meninges. Opportunistic infections and bugs with capsular infections and bugs with capsular polysaccharide Ag’spolysaccharide Ag’s

Poor response to polysaccharide antigens Poor response to polysaccharide antigens but normal IgGbut normal IgG22

(So look for Ab’s, not IgG subclasses)(So look for Ab’s, not IgG subclasses) Xp11.22-11.23Xp11.22-11.23 WASP gene binds lots of signaling WASP gene binds lots of signaling

moleculesmolecules

XL Lymphoproliferative DzXL Lymphoproliferative Dz

T and B cellT and B cell SLAM-SAP interaction (costimulatory SLAM-SAP interaction (costimulatory

signaling) problemssignaling) problems

Hyper IgEHyper IgE

Abscesses (staph), esp skin (boils) Abscesses (staph), esp skin (boils) but also lungbut also lung

Lung abscesses progressing to giant Lung abscesses progressing to giant cysts/pneumatocoeles.cysts/pneumatocoeles.

No diagnostic test; markedly No diagnostic test; markedly elevated levels of IgE are even seen elevated levels of IgE are even seen in atopic dermatitisin atopic dermatitis

DiGeorgeDiGeorge

Associated abnormalities of face, Associated abnormalities of face, brain, thymus, parathyroid, brain, thymus, parathyroid, heart/aorta (and platelets!)heart/aorta (and platelets!)

FISH for 11q22FISH for 11q22 Hypocalcemia, seizuresHypocalcemia, seizures Extremely variable phenotypeExtremely variable phenotype

SCIDSCID Stem cells defective or absentStem cells defective or absent OR T helpers defective or absentOR T helpers defective or absent OR thymus defective or absent (no T cell OR thymus defective or absent (no T cell

maturationmaturation B cells are affected because there’s no T B cells are affected because there’s no T

helphelp ADA def: no T or B cellsADA def: no T or B cells PNP (purine nucleoside phosphorolase): PNP (purine nucleoside phosphorolase):

much more T cellmuch more T cell Invasive infections and really serious viral Invasive infections and really serious viral

infections; PCPinfections; PCP

Ataxia-TelangiectasiaAtaxia-Telangiectasia

T and B cells; usually have abnormal T and B cells; usually have abnormal Ig’s (A or E; some G)Ig’s (A or E; some G)

Ataxic first, then develop Ataxic first, then develop telangiectasia, especially of eyetelangiectasia, especially of eye

Infections of lungs, sinuses; with Infections of lungs, sinuses; with bacteria and virusesbacteria and viruses

Increased AFP levelIncreased AFP level

From ABP From ABP Certifying Exam Content OutlineCertifying 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

CreditsCredits

Meghen Browning MDMeghen Browning MD