Immune deficiency Immune deficiency syndromessyndromes

Keri C. SmithKeri C. Smith

May 28, 2009May 28, 2009

Immune deficienciesImmune deficiencies

PrimaryPrimary Hereditary or acquiredHereditary or acquired

• Can be categorized based on clinical presentationCan be categorized based on clinical presentation Cell mediated (T cell)Cell mediated (T cell) Antibody mediated (B cell)Antibody mediated (B cell) Nonspecific (phagocytes, NK cells)Nonspecific (phagocytes, NK cells) Complement activationComplement activation

SecondarySecondary Immune deficiency is the result of another Immune deficiency is the result of another

diseasedisease

Major clinical manifestations of Major clinical manifestations of immune disordersimmune disorders

DisorderDisorder Associated DiseaseAssociated Disease

DeficiencyDeficiency

B cell deficiency – deficiency in Ab B cell deficiency – deficiency in Ab mediated immunitymediated immunity

Recurrent bacterial disease (otitis Recurrent bacterial disease (otitis media, recurrent pneumoniamedia, recurrent pneumonia

T Lymphocyte deficiency – deficiency in T Lymphocyte deficiency – deficiency in cell mediated immunitycell mediated immunity

Increased susceptibility to viral, Increased susceptibility to viral, fungal,protozoal infectionfungal,protozoal infection

T and B lymphocyte deficiency – T and B lymphocyte deficiency – combined deficiency of Ab- and cell-combined deficiency of Ab- and cell-mediated immunitymediated immunity

Acute and chronic infections with viral, Acute and chronic infections with viral, bacterial, fungal, and protozoal bacterial, fungal, and protozoal organismsorganisms

Phagocytic cell deficiencyPhagocytic cell deficiency Systemic infections with bacteria of Systemic infections with bacteria of usually low virulence, infections with usually low virulence, infections with pyogenic bacteria, impaired pus pyogenic bacteria, impaired pus formation and would healingformation and would healing

NK cell deficiencyNK cell deficiency Viral infections, associated with several Viral infections, associated with several T cell disorders and X-linked T cell disorders and X-linked lymphoproliferative syndromeslymphoproliferative syndromes

Complement component deficiencyComplement component deficiency Bacterial infections;autommunityBacterial infections;autommunity

SSevere evere CCombined ombined IImmunodeficiency mmunodeficiency DDisease (SCID)isease (SCID)

Life threatening infections soon after birthLife threatening infections soon after birth Wasting, Failure to thriveWasting, Failure to thrive Lack of Thymic shadowLack of Thymic shadow Lack of CD3+, CD4+, CD8+ and Lack of CD3+, CD4+, CD8+ and

lymphocyte response to antigenslymphocyte response to antigens

““The Boy in the Bubble”The Boy in the Bubble”

Primary immunodeficienciesPrimary immunodeficiencies SSevere evere CCombined ombined IImmunodeficiency mmunodeficiency

DDiseaseisease T-B+T-B+

• X-linked SCID (40-50% of cases)X-linked SCID (40-50% of cases) Lack Lack chain for common cytokine receptor chain for common cytokine receptor

• Autosomal recessive SCIDAutosomal recessive SCID Mutation in gene that encodes JAK3 tyrosine kinaseMutation in gene that encodes JAK3 tyrosine kinase

X linked and autosomal recessiveX linked and autosomal recessive

Primary immunodeficiencyPrimary immunodeficiency

SSevere evere CCombined ombined IImmunodeficiency mmunodeficiency DDiseaseisease T-B-T-B-

• Adenosine deaminase deficiency (20% of cases)Adenosine deaminase deficiency (20% of cases) Missing housekeeping enzyme in purine salvage pathway, Missing housekeeping enzyme in purine salvage pathway,

autosomal recessive, buildup of toxic wastes affects B and T autosomal recessive, buildup of toxic wastes affects B and T cellscells

• Purine nucleoside phosphorylase deficiencyPurine nucleoside phosphorylase deficiency Purine salvage pathway, toxic wastes affect neurologic system Purine salvage pathway, toxic wastes affect neurologic system

and T cells (these patients have autoimmunity?!)and T cells (these patients have autoimmunity?!)

• Recombinase deficiencyRecombinase deficiency RAG 1 and 2 required for the rearrangement of Ig genes and RAG 1 and 2 required for the rearrangement of Ig genes and

TCR. Cells are stuck in pre-B and pre-T stages. NK cell TCR. Cells are stuck in pre-B and pre-T stages. NK cell function OKfunction OK

Primary ImmunodeficiencyPrimary Immunodeficiency

SSevere evere CCombined ombined IImmunodeficiency mmunodeficiency DDiseaseisease T+B-T+B-

• Omenn syndromeOmenn syndrome ““leaky” SCID with partial RAG activity. Th2 imbalance leaky” SCID with partial RAG activity. Th2 imbalance

and a tendency towards hyper IgE syndromeand a tendency towards hyper IgE syndrome

T+B+T+B+• Bare lymphocyte syndromeBare lymphocyte syndrome

Failure to express HLA moleculesFailure to express HLA molecules

• ZAP-70 mutationZAP-70 mutation Unable to signal through TCRUnable to signal through TCR

Failure to stimulate T cellsFailure to stimulate T cells

Multisystem disordersMultisystem disorders

Wiskott-Aldrich SyndromeWiskott-Aldrich Syndrome X linked mutation in gene encoding protein that interacts with X linked mutation in gene encoding protein that interacts with

cytoskeletoncytoskeleton Bleeding, recurrent bacterial infections, allergic reactionsBleeding, recurrent bacterial infections, allergic reactions Abnormal B and T cells, low T cell countAbnormal B and T cells, low T cell count Can be treated with antibiotics, antivirals, bone marrow Can be treated with antibiotics, antivirals, bone marrow

transplanttransplant Ataxia TelangiectasiaAtaxia Telangiectasia

Mutation in ATM geneMutation in ATM gene Manifests as staggering gait with abnormal vascular dilationManifests as staggering gait with abnormal vascular dilation Increased susceptibility to infection, lymphopenia, depressed Ig Increased susceptibility to infection, lymphopenia, depressed Ig

and T cell responseand T cell response

Treatment for SCIDTreatment for SCID

Bone marrow/ placental stem cell Bone marrow/ placental stem cell transplanttransplant

IvIg if necessaryIvIg if necessary Supportive careSupportive care Gene therapy, if possibleGene therapy, if possible Avoid live viral vaccines!Avoid live viral vaccines! CMV-/irradiated/low WBC blood CMV-/irradiated/low WBC blood

transfusionstransfusions

Future research directions….Future research directions….

Careful consideration of patientsDifferent vectors?Monitor patients for insertion sitesStem cells?

Immunodeficiencies of T cells and Immunodeficiencies of T cells and cell -mediated immunitycell -mediated immunity

Patients are susceptible to viral, fungal, Patients are susceptible to viral, fungal, and protozoal infectionsand protozoal infections

Often exhibit selective defects in Ab Often exhibit selective defects in Ab productionproduction

Can be difficult to distinguish from SCID Can be difficult to distinguish from SCID patientspatients

DiGeorge syndromeDiGeorge syndrome

Congenital thymic aplasia – thymus does not develop Congenital thymic aplasia – thymus does not develop normally (neither does parathyroid) 1:4000normally (neither does parathyroid) 1:4000

Results from deletion in chromosome 22q11, but is not Results from deletion in chromosome 22q11, but is not inheritedinherited

Few to no mature T cells in peripheryFew to no mature T cells in periphery Symptoms:Symptoms:

HypocalcemiaHypocalcemia Congenital cardiac diseaseCongenital cardiac disease Recurrent or chronic infections with viruses, bacteria, fungi, Recurrent or chronic infections with viruses, bacteria, fungi,

protozoaprotozoa Lack of immune response after immunization with T dependent Lack of immune response after immunization with T dependent

antigensantigens

Former treatment of DiGeorge Former treatment of DiGeorge syndromesyndrome

Fetal thymus graft (<14 weeks gestation)Fetal thymus graft (<14 weeks gestation) Why did this result in functional T cells?Why did this result in functional T cells?

Donor fetal thymus provided thymic epithelial cells, and patient’s T cells had an environment to mature

Why did the T cells “collaborate” poorly with Why did the T cells “collaborate” poorly with patient APC?patient APC?

Patient T cells recognized the MHC of the donor as “self”, not the patient MHC.

Nude MiceNude Mice

Mouse model for DiGeorge syndromeMouse model for DiGeorge syndrome

T cell deficiencies with normal T cell deficiencies with normal peripheral T cell numbersperipheral T cell numbers

Functional, rather than numerical defect in Functional, rather than numerical defect in T cell populationT cell population

Susceptible to opportunistic infections, Susceptible to opportunistic infections, high incidence of autoimmune diseasehigh incidence of autoimmune disease

Autosomal recessiveAutosomal recessive Deficient expression in:Deficient expression in:

• ZAP-70 tyrosine kinase (phenotype includes CD8 ZAP-70 tyrosine kinase (phenotype includes CD8 deficiency and SCID-like symptomsdeficiency and SCID-like symptoms

• CD3CD3• CD3CD3

ALPSALPS

Autoimmune Lymphoproliferative DisorderAutoimmune Lymphoproliferative Disorder Systemic autoimmune disease, Systemic autoimmune disease,

susceptible only to chronic viral infectionssusceptible only to chronic viral infections Increased CD4-/CD8- T cells, can develop Increased CD4-/CD8- T cells, can develop

B cell lymphomasB cell lymphomas Most patients have a mutation in gene Most patients have a mutation in gene

encoding for encoding for Fas Fas (CD95)(CD95)

Chronic Mucocutaneous Chronic Mucocutaneous CandidiasisCandidiasis

Poorly defined collection of syndromes Poorly defined collection of syndromes characterized by characterized by CandidaCandida infections of infections of skin and mucous membranesskin and mucous membranes

Normal B cell immunity, and normal T cell Normal B cell immunity, and normal T cell immunity (to everything other than immunity (to everything other than Candida)Candida)

May be inherited, affects predominantly May be inherited, affects predominantly childrenchildren

B cell or Ig-associated B cell or Ig-associated ImmunodeficiencyImmunodeficiency

May be associated with defective B cell May be associated with defective B cell development (absence of all Ig development (absence of all Ig subclasses) or deficiency in subclass or subclasses) or deficiency in subclass or class of Igclass of Ig

Patients suffer from recurrent or chronic Patients suffer from recurrent or chronic infectionsinfections

Brunton’s agammaglobulinemiaBrunton’s agammaglobulinemia

X-linked infantile agmmaglobulinemiaX-linked infantile agmmaglobulinemia 1:100,0001:100,000 Noticed in infants at 5-6 months of ageNoticed in infants at 5-6 months of age Serious and repeated bacterial infectionsSerious and repeated bacterial infections Defect in BTK geneDefect in BTK gene

Pre-B cells cannot develop into mature B cellsPre-B cells cannot develop into mature B cells Treatment consists of IvIg injections, but Treatment consists of IvIg injections, but

chronic lung disease is a problemchronic lung disease is a problem

Transient HypogammaglobulinemiaTransient Hypogammaglobulinemia

Normal number of B cells in bloodNormal number of B cells in blood Transient inability to produce IgGTransient inability to produce IgG May be due to deficiency in number and May be due to deficiency in number and

function of helper T cellsfunction of helper T cells Does not usually persist past 2 yearsDoes not usually persist past 2 years

CVIDCVID

Common Variable Immunodeficiency DiseaseCommon Variable Immunodeficiency Disease Onset 15-35 years, decreased serum IgA, IgG, low to Onset 15-35 years, decreased serum IgA, IgG, low to

normal IgMnormal IgM Pneumonia, bronchiectasis, sinusitis, GI infectionsPneumonia, bronchiectasis, sinusitis, GI infections May also have autoantibodies, SLE, higher incidence of May also have autoantibodies, SLE, higher incidence of

cancercancer Caused by failure of B cells to mature to Ab secreting Caused by failure of B cells to mature to Ab secreting

cells cells Class II MHC 6Class II MHC 6thth chromosome chromosome ICOS gene (5%)ICOS gene (5%) TACI gene (15%)TACI gene (15%)

Treatment with IvIgTreatment with IvIg

IgA deficiencyIgA deficiency

1:800 incidence1:800 incidence Lack of serum and mucosal IgALack of serum and mucosal IgA Usually asymptomaticUsually asymptomatic GI, respiratory diseaseGI, respiratory disease Associated with allergy, autoimmunityAssociated with allergy, autoimmunity Etiology unknown, but familial associations Etiology unknown, but familial associations

and linkage with CVIDand linkage with CVID Broad spectrum antibioticsBroad spectrum antibiotics

Association between CVID and IgADAssociation between CVID and IgAD

Patients with IgA deficiency are usually treated Patients with IgA deficiency are usually treated with broad-spectrum antibiotics. Why is the with broad-spectrum antibiotics. Why is the

injection of IgA not a suitable treatment in these injection of IgA not a suitable treatment in these patients?patients?

A.A. Serum sickness will occurSerum sickness will occur

B.B. IgA isn’t a good activator of complement, and IgA isn’t a good activator of complement, and thus is useless against bacterial infectionsthus is useless against bacterial infections

C.C. Injected IgA is unlikely to be secreted at the Injected IgA is unlikely to be secreted at the mucosal immune surfacesmucosal immune surfaces

D.D. A,B,and CA,B,and C

E.E. A and CA and C

Treatment of Ig deficiency Treatment of Ig deficiency disordersdisorders

IvIgIvIg Supportive care (antibiotics)Supportive care (antibiotics) No live viral vaccines!No live viral vaccines! Complications include malignancies, Complications include malignancies,

autoimmunityautoimmunity

Hyper IgM syndromeHyper IgM syndrome

Mostly males, rarely femalesMostly males, rarely females Severe respiratory infections, sinusitis, Severe respiratory infections, sinusitis,

diagnosed age 1-2diagnosed age 1-2 Very low serum IgG, IgE, IgA, and normal Very low serum IgG, IgE, IgA, and normal

to elevated IgMto elevated IgM T cell immunity can weaken with timeT cell immunity can weaken with time Abnormal germinal center formationAbnormal germinal center formation Complications include malignancy, Complications include malignancy,

autoimmunityautoimmunity

The many causes of Hyper IgMThe many causes of Hyper IgM

Duncan SyndromeDuncan Syndrome

X-linked lymphoproliferative diseaseX-linked lymphoproliferative disease Originally observed in 6 maternally related Originally observed in 6 maternally related

males of the Duncan familymales of the Duncan family T cells can’t regulate B cell growthT cells can’t regulate B cell growth Exposure to EBV results in severe Exposure to EBV results in severe

infectious mononucleosisinfectious mononucleosis High probability of lymphoma developmentHigh probability of lymphoma development Poor prognosisPoor prognosis

Phagocytic dysfunctionsPhagocytic dysfunctions

Affect the innate and acquired response to Affect the innate and acquired response to pathogenspathogens

Dysfunction in:Dysfunction in: Action required to phagocytizeAction required to phagocytize Migration and adhesion of phagocytic cellsMigration and adhesion of phagocytic cells

LADLAD Leukocyte adhesion deficiencyLeukocyte adhesion deficiency Autosomal recessiveAutosomal recessive Group of disorders in which the leukocyte Group of disorders in which the leukocyte

interaction with vascular endothelium is interaction with vascular endothelium is disrupteddisrupted subunit of integrinssubunit of integrins Selectin ligands Selectin ligands

Consequences:Consequences: Recurrent soft tissue bacterial infectionRecurrent soft tissue bacterial infection Increased blood WBC countsIncreased blood WBC counts No pus formation or effective wound healingNo pus formation or effective wound healing

BLADBLAD

Early 1990’s – up to Early 1990’s – up to 15% of Holstein bulls 15% of Holstein bulls and 6-8% of cows and 6-8% of cows were carriers for were carriers for mutated CD18 genemutated CD18 gene

Up to 20,000 Up to 20,000 calves/year potentially calves/year potentially affectedaffected

Screening for the Screening for the affected gene reduced affected gene reduced incidenceincidence

Chediak-Higashi SyndromeChediak-Higashi Syndrome

Autosomal recessiveAutosomal recessive Abnormal giant granules and organelles in the Abnormal giant granules and organelles in the

cellcell Diminished killing of intracellular organisms Diminished killing of intracellular organisms

(lysosomes and degranulation), leading to (lysosomes and degranulation), leading to massive infiltration of lymphocytes and massive infiltration of lymphocytes and macrophages in liver, spleen, lymph nodesmacrophages in liver, spleen, lymph nodes

Strep and Staph main problem – recurrent Strep and Staph main problem – recurrent infectionsinfections

Poor prognosisPoor prognosis

Chronic Granulomatous DiseaseChronic Granulomatous Disease

X-linked, autosomal X-linked, autosomal recessiverecessive

Skin, lymph node, lung Skin, lymph node, lung infectionsinfections

High WBC in bloodHigh WBC in blood Phagocytes unable to Phagocytes unable to

complete respiratory burstcomplete respiratory burst Treatments include Treatments include

antibiotics, antifungals, IFNantibiotics, antifungals, IFN

Summary of phagocytic dysfunctionSummary of phagocytic dysfunction

Complement AbnormalitiesComplement Abnormalities

Deficiencies inherited in autosomal Deficiencies inherited in autosomal fashion, heterozygotes have 50% of given fashion, heterozygotes have 50% of given complement proteincomplement protein

Complement is required for:Complement is required for: Opsonization and killing of bacteriaOpsonization and killing of bacteria ChemotaxisChemotaxis B cell activationB cell activation Elimination of Ag-Ab complexesElimination of Ag-Ab complexes

Early complement protein Early complement protein deficienciesdeficiencies

C1, C2, C4 or C3 deficiencyC1, C2, C4 or C3 deficiency Pyogenic infectionsPyogenic infections Autoimmunity – SLE very commonAutoimmunity – SLE very common

Late complement protein Late complement protein deficienciesdeficiencies

C5-C9C5-C9 Prevents formation of membrane attack Prevents formation of membrane attack

complexcomplex Gram negative bacterial infectionsGram negative bacterial infections

Diagnosis of immune deficiency Diagnosis of immune deficiency disorders disorders

Medical HistoryMedical History Age at onsetAge at onset Live vaccines?Live vaccines? Family historyFamily history Severity of illnessSeverity of illness

Physical ExamPhysical Exam Tonsils?Tonsils? OrganomegalyOrganomegaly Palpate lymph nodesPalpate lymph nodes Chart growthChart growth Chest X rayChest X ray

Lab testsLab tests PhagocytePhagocyte

Cell surface markersCell surface markers Bacteriocidal assayBacteriocidal assay Chemotaxis and opsonization Chemotaxis and opsonization

assaysassays

NK and MacrophageNK and Macrophage 5151Cr release assaysCr release assays Cytokine releaseCytokine release

Ig functionIg function IsohemagluttininsIsohemagluttinins DT, TT responseDT, TT response Anti-pneumococcusAnti-pneumococcus Ig levelsIg levels molecular/DNA studiesmolecular/DNA studies

B cell functionB cell function CD27 memory cellsCD27 memory cells Nucleic acid enzyme assaysNucleic acid enzyme assays molecular/DNA studiesmolecular/DNA studies

T cell functionT cell function DTHDTH Flow cytometry for subsetsFlow cytometry for subsets PHA/Ag stimulationPHA/Ag stimulation TCR spectratypingTCR spectratyping

Acquired ImmunodeficienciesAcquired Immunodeficiencies

Secondary immune deficiencies that are Secondary immune deficiencies that are the consequences of other diseasesthe consequences of other diseases MalnutritionMalnutrition Chemotherapeutic agentsChemotherapeutic agents Deliberate immunosuppressionDeliberate immunosuppression Untreated autoimmunityUntreated autoimmunity Overwhelming bacterial infectionOverwhelming bacterial infection

HIVHIV

HIV binding, replicationHIV binding, replication

Gp120 binds CD4Gp120 binds CD4 Coreceptor bindingCoreceptor binding

CCR5 (macrophage tropic)CCR5 (macrophage tropic) CXCR4 (lymphtropic)CXCR4 (lymphtropic)

Penetration of cell Penetration of cell membranemembrane

Transcription of RNA to Transcription of RNA to CDNA, remains in latent CDNA, remains in latent phasephase

Activated T cells, viral Activated T cells, viral replication and releasereplication and release

Macrophages, DC generally Macrophages, DC generally serve as reservoirsserve as reservoirs

Clinical course of HIV infectionClinical course of HIV infection Acute infectionAcute infection

Asymptomatic or flu-like illnessAsymptomatic or flu-like illness Drop in circulating CD4 cells, CTLs and Ab increaseDrop in circulating CD4 cells, CTLs and Ab increase SeroconversionSeroconversion

Chronic latent phaseChronic latent phase Up to 15 yearsUp to 15 years Low level of viral replication, gradual loss of CD4 cellsLow level of viral replication, gradual loss of CD4 cells

Crisis phaseCrisis phase Characterized by unusual malignancies, opportunistic infections, Characterized by unusual malignancies, opportunistic infections,

neurologic sundromesneurologic sundromes Activation of virally infected T cells by Ag results in stimulation of Activation of virally infected T cells by Ag results in stimulation of

viral transcription and progeny formation, accelerates T cell viral transcription and progeny formation, accelerates T cell deathdeath

Also increases viral mutation rate (escape mutants)Also increases viral mutation rate (escape mutants)

Diagnosis of HIV infectionDiagnosis of HIV infection

Also, CD4 count of <200/ml indicates full-blown AIDS

AIDS associated diseasesAIDS associated diseases InfectionsInfections

FungalFungal• CandidiasisCandidiasis• CryptococcosisCryptococcosis• HistoplasmosisHistoplasmosis• CoccidiodomycosisCoccidiodomycosis

ParasiticParasitic• ToxoplasmosisToxoplasmosis• PneumocystisPneumocystis• CryptosporidiosisCryptosporidiosis• IsoporiasisIsoporiasis

BacterialBacterial• Mycobacteriosis (including Mycobacteriosis (including

atypical atypical SalmonellaSalmonella)) ViralViral

• CytomegalovirusCytomegalovirus• Herpes simplexHerpes simplex• Progressive multifocal Progressive multifocal

leukoencephalopathyleukoencephalopathy

NeoplasmsNeoplasms SarcomaSarcoma

• Kaposi’s sarcomaKaposi’s sarcoma LymphomaLymphoma

• Burkitt lymphomaBurkitt lymphoma• Diffuse large B cell lymphomaDiffuse large B cell lymphoma• Effusion-based lymphomaEffusion-based lymphoma• Primary CNS lymphomaPrimary CNS lymphoma

CarcinomaCarcinoma• Invasive cancer of the uterine Invasive cancer of the uterine

cervixcervix General conditionsGeneral conditions

HIV encephalopathy and HIV encephalopathy and dementiadementia

Wasting syndromeWasting syndrome

Current treatments for HIVCurrent treatments for HIV

Prevention and control of HIVPrevention and control of HIV Test blood donationsTest blood donations Condom useCondom use HIV+ pregnant women placed on anti-viral therapyHIV+ pregnant women placed on anti-viral therapy

TherapyTherapy AZT (nucleoside inhibitor of reverse transcriptase)AZT (nucleoside inhibitor of reverse transcriptase) HAART (triple-agent anti-viral therapy, three drugs HAART (triple-agent anti-viral therapy, three drugs

from two inhibitor classes)from two inhibitor classes)