An overview of primary immunodeficiency diseases 2014
description
Transcript of An overview of primary immunodeficiency diseases 2014
In the Name of God the Merciful the BneficientIn the Name of God the Merciful the Bneficient
Overview of Primary Overview of Primary Immunodeficiency Immunodeficiency
DisordersDisorders((PIDsPIDs))
Mostafa Moin MDMostafa Moin MDProfessor of Allergy & Clinical Immunology Professor of Allergy & Clinical Immunology
Immunology, Asthma & Research InstituteImmunology, Asthma & Research Institute
IAARIIAARI
Tehran Univesity of Medical SciencesTehran Univesity of Medical Sciences13921392-- 20142014
Key Roles of Immune SystemKey Roles of Immune System
Prevent and control Prevent and control infectioninfection Prevent and control Prevent and control autoimmune diseasesautoimmune diseases Prevent and control Prevent and control malignancymalignancy Prevent and control Prevent and control allergic diseasesallergic diseases Prevent and control Prevent and control graft-versus-host (GVH)graft-versus-host (GVH)
Host Immune Defense MechanismsHost Immune Defense Mechanisms
Non-specificNon-specific --InnateInnate BarriersBarriers
– SkinSkin– Secretions (mucous, Secretions (mucous,
tears, saliva)tears, saliva)– Mucociliary clearance, Mucociliary clearance,
peristalsisperistalsis PhagocytesPhagocytes
– NeutrophilsNeutrophils– MacrophagesMacrophages
ComplementComplement CytokinesCytokines
Specific -Specific - Acquired Acquired HumoralHumoral (antibodies) (antibodies)
CellularCellular (lymphocytes)(lymphocytes)
Innate and Acquired ImmunityInnate and Acquired Immunity
InnateInnate AcquiredAcquired
Ag specificityAg specificity nono yesyes
Magnitude (Magnitude (1100, , 2200)) samesame higher (higher (2200 > > 1100))
MemoryMemory nono yesyes
Key componentsKey components PMN, NKPMN, NK T, B lymphocytesT, B lymphocytesC’, C’, barriersbarriers APCsAPCs
Cytokines, Chemokines,Adhesion molecules
Types of Immuno-deficienciesTypes of Immuno-deficiencies
6
Defects in some components of the immune systemDefects in some components of the immune system
- - Gene defectGene defect
Increased frequency, severity and Increased frequency, severity and duration of duration of infectioninfection
Unexpected Unexpected complicationscomplications or unusual or unusual manifestations of infectionmanifestations of infection
Infection with Infection with organismsorganisms normally normally considered of considered of low pathogenicitylow pathogenicity
Noninfectious manifestationsNoninfectious manifestations in in gastrointestinal, endocrinologic, gastrointestinal, endocrinologic, hematologic organ systemshematologic organ systems
Clinical Features of Primary ImmunodeficiencyClinical Features of Primary Immunodeficiency
Recurrent respiratory infectionRecurrent respiratory infection Persistent sinus infectionPersistent sinus infection Paucity of lymphoid tissuePaucity of lymphoid tissue Failure-to-thrive in infantsFailure-to-thrive in infants Skin lesions (rash, pyoderma, eczema, Skin lesions (rash, pyoderma, eczema,
telangiectasia)telangiectasia) Oral and perineal candidiasisOral and perineal candidiasis Diarrhea and malabsorptionDiarrhea and malabsorption
Clinical Findings in Primary ImmunodeficiencyClinical Findings in Primary Immunodeficiency
Accurate diagnosis and Accurate diagnosis and classification of PID is necessaryclassification of PID is necessary
To decide on appropriate To decide on appropriate clinical managementclinical management
To enable ininformed To enable ininformed genetic counselinggenetic counseling
To permit the systematic collection of data on PID To permit the systematic collection of data on PID through through registriesregistries that will facilitate further study that will facilitate further study of these rare diseasesof these rare diseases
To highlight the advances in To highlight the advances in gene therapygene therapy
9
WHY?
PIDs PrevalencePIDs Prevalence
Texbooks report Texbooks report 1 in 100001 in 10000 1999 U.S. Immunodeficiency Foundation 1999 U.S. Immunodeficiency Foundation
Survey found Survey found 1 in 50001 in 5000 2007 telephone survey of 27000 2007 telephone survey of 27000
household members found household members found 1 in 12001 in 1200 Antibody deficienciesAntibody deficiencies account for account for
approximately approximately 65%65% of PID cases of PID cases
International Union of Immunological SocietiesInternational Union of Immunological Societies New York City, May 31-June 1, 2011New York City, May 31-June 1, 2011
Table 1 | Table 1 | Combined immunodeficienciesCombined immunodeficienciesTable 2 | Table 2 | Well-defined syndromes with immunodef.Well-defined syndromes with immunodef.Table 3 | Table 3 | Predominantly antibody deficienciesPredominantly antibody deficienciesTable 4 | Table 4 | Diseases of immune dysregulationDiseases of immune dysregulationTable 5 | Table 5 | Congenital defects of phagocyte number,Congenital defects of phagocyte number, function, or bothfunction, or bothTable 6 | Table 6 | Defects in innate immunityDefects in innate immunityTable 7 | Table 7 | Autoinflammatory disordersAutoinflammatory disordersTable 8 | Table 8 | Complement deficienciesComplement deficiencies
PID Classification:2011-IUISPID Classification:2011-IUIS
Immunopathologic Basis of PIDImmunopathologic Basis of PID
Four Major Host Defense DeficienciesFour Major Host Defense Deficiencies
2.2. T-cell or combined T-cell or combined immunodeficienciesimmunodeficiencies
3.3. Phagocyte disordersPhagocyte disorders
4.4. Complement disordersComplement disorders
1.1. B-cell (B-cell (humoral) immunodeficiencieshumoral) immunodeficiencies
IgG Antibody Levels Vary with AgeIgG Antibody Levels Vary with Age
Rules of thumb:Rules of thumb:-Quantitative IgG< 1000 is abnormalQuantitative IgG< 1000 is abnormal-Quantitative IgM< 100 is abnormalQuantitative IgM< 100 is abnormal-Quantitative IgA< 10 is abnormalQuantitative IgA< 10 is abnormal
Deficient Serum Antibody LevelDeficient Serum Antibody Level
Symptoms of antibody deficiencySymptoms of antibody deficiency
RecurrentRecurrent upper and lower respiratory upper and lower respiratory infectionsinfections
Severe bacterial infections with Severe bacterial infections with polysaccharide encapsulated bacteriapolysaccharide encapsulated bacteria
Paucity of lymph nodes Paucity of lymph nodes and tonsilsand tonsils Immune cytopeniasImmune cytopenias AutoimmunityAutoimmunity - arthritis, SLE - arthritis, SLE DiarrheaDiarrhea and malabsorption and malabsorption
MalignanciesMalignancies
BacteriaBacteria:: pneumococcus, H. flu, pneumococcus, H. flu, meningococcus, Staph aureus, meningococcus, Staph aureus, Pseudomonas, CampylobacterPseudomonas, Campylobacter
MycoplasmaMycoplasma, ureaplasma, ureaplasma VirusesViruses:: enterovirusesenteroviruses, rotavirus, rotavirus ProtozoaProtozoa:: giardia, cryptosporidium giardia, cryptosporidium Common organismsCommon organisms are still the most are still the most
common - but typically more severe and common - but typically more severe and difficult to treatdifficult to treat
Antibody Deficiency Infectious OrganismsAntibody Deficiency Infectious Organisms
Agammaglobinemias (XL,ARAgammaglobinemias (XL,AR)) Common Variable ImmunodeficiencyCommon Variable Immunodeficiency IgA deficiencyIgA deficiency IgG subclass deficiencyIgG subclass deficiency Specific antibody deficiencySpecific antibody deficiency Transient hypogammaglobinemia of Transient hypogammaglobinemia of
infancyinfancy
PrimaryPrimary Antibody DisordersAntibody Disorders
Antibody def.-Bruton's diseaseAntibody def.-Bruton's disease
X-linked agammaglobulinemia X-linked agammaglobulinemia (XLA)(XLA) Marked reductionMarked reduction in in all Ig classesall Ig classes, , B cell numbersB cell numbers
& & production of specific antibodiesproduction of specific antibodies Normal number and function of T cellsNormal number and function of T cells Defect in Bruton`s tyrosine kinase geneDefect in Bruton`s tyrosine kinase gene, B cell , B cell
development “frozen” at early precursor stagedevelopment “frozen” at early precursor stage Beginning Beginning after 6 months after 6 months of age,recurrentof age,recurrent
sino-pulmonary Infectionssino-pulmonary Infections
Antibody def.-Bruton's diseaseAntibody def.-Bruton's disease
DiarrheaDiarrhea due to giardia, due to giardia, Invasive infections Invasive infections
(sepsis, meningitis) due to encapsulated bacteria (sepsis, meningitis) due to encapsulated bacteria (pneumococcus, meningococcus)(pneumococcus, meningococcus)
Skin/soft tissue infectionsSkin/soft tissue infections Generally no increased severity of viral infections,Generally no increased severity of viral infections,
but at risk for chronic multisystem inf. due tobut at risk for chronic multisystem inf. due to
enteroviruses enteroviruses (including dermatomyositis- like (including dermatomyositis- like
synd. , hepatitis,meningoencephalitissynd. , hepatitis,meningoencephalitis))
Antibody: Common variable Antibody: Common variable
immunodeficiency immunodeficiency -- CVIDCVID
OnsetOnset usually in usually in 2nd to 4th decade 2nd to 4th decade of lifeof life Slow decline Slow decline in all classes of immunoglobulinin all classes of immunoglobulin Recurrent sinopulmonary Recurrent sinopulmonary infections (usually infections (usually
bacterial in origin)bacterial in origin) Gastrointestinal, endocrine, hematologic and Gastrointestinal, endocrine, hematologic and
autoimmune disorders autoimmune disorders can be associatedcan be associated May follow May follow Epstein-Barr infectionEpstein-Barr infection Increased incidence of Increased incidence of lymphoreticular malignancieslymphoreticular malignancies Genetic defect?Genetic defect?
Antibody: IgA deficiency Antibody: IgA deficiency
IgA< 5 IgA< 5 mg/dlmg/dl Most common Most common (1:400- 1:1000)(1:400- 1:1000) Often asymptomaticOften asymptomatic, may have recurrent , may have recurrent
sinopulmonary infectionssinopulmonary infections May co-exist with IgG subclass deficiencyMay co-exist with IgG subclass deficiency AllergyAllergy / / autoimmunityautoimmunity No treatmentNo treatment (only for infections) (only for infections) Genetic defect?Genetic defect?
Transient hypogammaglobulinemia of infancyTransient hypogammaglobulinemia of infancy- Maturational delayMaturational delay with low, persistent nadir in Ig production: with low, persistent nadir in Ig production:
normal event in preterm infantsnormal event in preterm infants- Usually Usually recurrent sinopulmonary infectionsrecurrent sinopulmonary infections- Usually normal B cell numberUsually normal B cell number and and response to immunizationresponse to immunization IgG subclass deficiencyIgG subclass deficiency- Commonly overdiagnosedCommonly overdiagnosed but may be significant if specific but may be significant if specific
antibody production also lowantibody production also low- IgG2, 4-infection with encapsulated bacteriaIgG2, 4-infection with encapsulated bacteria- IgG3-recurrent respiratory infectionsIgG3-recurrent respiratory infections- May occur in association with IgA deficiencyMay occur in association with IgA deficiency and evolve to and evolve to
common variable immunodeficiencycommon variable immunodeficiency
Antibody deficienciesAntibody deficiencies
Antibody: Hyper IgM SyndromeAntibody: Hyper IgM Syndrome
X-linkedX-linked, , defect in CD40 ligand defect in CD40 ligand expression (CD1540)expression (CD1540) 1: 500000, 90% by age 4 yrs old1: 500000, 90% by age 4 yrs old Recurrent sinopulmonary and invasive infections due to Recurrent sinopulmonary and invasive infections due to
encapsulated bacteriaencapsulated bacteria Recurrent neutropenia Recurrent neutropenia associated with oral ulcers and perirectal associated with oral ulcers and perirectal
abscessesabscesses Opportunistic infections caused by Opportunistic infections caused by Pneumocystic jiroveciPneumocystic jiroveci, CMV, , CMV,
adenovirus, adenovirus, CryptococcusCryptococcus, and mycobacteria, and mycobacteria Chronic diarrhea due to Chronic diarrhea due to GiardiaGiardia or to or to Cryptosporidium,Cryptosporidium,
SalmonellaSalmonella, or , or EntamoebaEntamoeba histolyticahistolytica Markedly reduced IgG & IgAMarkedly reduced IgG & IgA; ; high or normal IgMhigh or normal IgM Normal numbers of B and T cellsNormal numbers of B and T cells
Secondary hypogammaglobulinemiaSecondary hypogammaglobulinemia
MedicationsMedications, especially anticonvulsants, especially anticonvulsants Protein-losing Protein-losing enteropathyenteropathy NephroticNephrotic syndrome syndrome IymphoproliferativeIymphoproliferative disease disease Non-Hodgkin`s Non-Hodgkin`s IymphomaIymphoma Multiple myelomaMultiple myeloma
CD4+ cells: CD4+ cells: – DTHDTH– Helper function for Helper function for
• Cellular cytotoxicityCellular cytotoxicity• Ig synthesisIg synthesis
CD8+ cells: CD8+ cells: – T-cell cytotoxicityT-cell cytotoxicity– T suppressor cellT suppressor cell
T cells/combined immunodeficiencyT cells/combined immunodeficiency
T cells/combined immunodeficiencyT cells/combined immunodeficiency
T cells required T cells required for orchestrating adaptive immunityfor orchestrating adaptive immunity Loss of CD4Loss of CD4 (helper) T cells results in (helper) T cells results in combined cellular combined cellular
and humoral immunodeficiencyand humoral immunodeficiency, even if B cells are normal, even if B cells are normal Deficiency results in infections with:Deficiency results in infections with:- virusesviruses-particularly herpes group-particularly herpes group- Intracellular bacteriaIntracellular bacteria-e.g., Mycobacteria, Listeria-e.g., Mycobacteria, Listeria- ProtozoansProtozoans-pneumocystis, toxoplasma, cryptosporidium, -pneumocystis, toxoplasma, cryptosporidium,
giardiagiardia Antibody production to newly encountered microbes also Antibody production to newly encountered microbes also
compromisedcompromised
Functional Classification T cells/combined Id.Functional Classification T cells/combined Id.
Severe Combined ImmunodeficiencySevere Combined Immunodeficiency
Presentation usuallyPresentation usually< 6-12 mo age< 6-12 mo age Opportunistis infections Opportunistis infections and recurrent pyogenic and recurrent pyogenic
infections, chronic infections, chronic
diarrhea , FTT, eczemadiarrhea , FTT, eczema Male:Male: female 4:1 (most common female 4:1 (most common
form is X-linked)form is X-linked) Often fatalOften fatal befor 1 year of age if untreated befor 1 year of age if untreated Decreased number of T cells, variable numbers of B Decreased number of T cells, variable numbers of B
cells, poor proliferation to mitogenscells, poor proliferation to mitogens Low or absent IgG and IgALow or absent IgG and IgA
(SCID)(SCID)
Severe deficits in Severe deficits in cellularcellular and and humoralhumoral immunity immunity Classified byClassified by inheritance patterninheritance pattern and and pattern of pattern of
lymphocytes presentlymphocytes present X-linked:X-linked: IL-2RIL-2Rγγ chain chain-more than half of all cases-more than half of all cases Same Same γγ chain found in many interleukin chain found in many interleukin
receptorsreceptors Autosomal recessiveAutosomal recessive:: RAG, ADA/PNP, JAK3, IL-7Ra, ZAP-70RAG, ADA/PNP, JAK3, IL-7Ra, ZAP-70
Severe Combined ImmunodeficiencySevere Combined Immunodeficiency(SCID)(SCID)
X-linked T- , NK, B+ phenotype 60% of SCID, gene identified in 1992 Defective gene encodes the cytokine common gamma chain Mild lymphopenia (mean ALC 1500) 40% have a positive family history Adenosine Dearninase (ADA) deficiency-AR 15% of all SCID Early onset Profound lymphopenia Clinically heterogeneous ADA is a widely expressed enzyme, involved in purine metabolism Build up of toxic metabolic products toxic to T cell development
Severe Combined ImmunodeficiencySevere Combined Immunodeficiency(SCID)(SCID)
RAG1 and RAG2 Deficiency- ARRAG1 and RAG2 Deficiency- AR T- , B-, NK+T- , B-, NK+ 10% of SCID genes identified in 198910% of SCID genes identified in 1989 RAG1 and RAG2 form a heterodimer that is required to initiate VDJ RAG1 and RAG2 form a heterodimer that is required to initiate VDJ
recombinationrecombination Moderate lymphopenia (mean ALC 1000)Moderate lymphopenia (mean ALC 1000) Amino acid substitutions can cause Omenn Syndrome (SCID with Amino acid substitutions can cause Omenn Syndrome (SCID with
hyper-eosinophilia)hyper-eosinophilia)
JAK-3JAK-3 T-, NK-, B+ phenotypeT-, NK-, B+ phenotype 7% of SCID gene identified in 19947% of SCID gene identified in 1994 Defective gene encodes a lyrosine kinase activated by the Defective gene encodes a lyrosine kinase activated by the
cytokine common gamma vhaincytokine common gamma vhain Mild lymphopenia (mean ALC 1500)Mild lymphopenia (mean ALC 1500)
Severe Combined ImmunodeficiencySevere Combined Immunodeficiency(SCID)(SCID)
Other Forms of T cell/combinedOther Forms of T cell/combined Immunodeficiency Immunodeficiency
Purine nucleoside phosphorylase (PNP) deficiency –ARPurine nucleoside phosphorylase (PNP) deficiency –AR Rare form of cellular deficiency associated with defective Ab Rare form of cellular deficiency associated with defective Ab
production and autoimmunityproduction and autoimmunity May present later in childhoodMay present later in childhood 2/3 of patients develop progressive neurological manifestations2/3 of patients develop progressive neurological manifestations
Ataxia- Telangiectasia- ARAtaxia- Telangiectasia- AR Mutation in protein required for DNA repairMutation in protein required for DNA repair Ocular telangiectasias, cerebellar ataxiaOcular telangiectasias, cerebellar ataxia Recurrent sinopulmonary infections: variable IgA, IgG2, IgG4 and Recurrent sinopulmonary infections: variable IgA, IgG2, IgG4 and
Tcell deficitsTcell deficits Risk of Malignancy in patients and carriersRisk of Malignancy in patients and carriers
Other Forms of T cell/combinedOther Forms of T cell/combined Immunodeficiency Immunodeficiency
DiGeorge Syndrome Developmental field defect of 3Developmental field defect of 3rdrd and 4 and 4thth branchial branchial
arches due to chromosomal deletion (22q)arches due to chromosomal deletion (22q) Cardiac/great vessel > parathyroid > thymic defectCardiac/great vessel > parathyroid > thymic defect Severe hypocalcemiaSevere hypocalcemia Charactristic facies: mandibular hypoplasia, Charactristic facies: mandibular hypoplasia,
hypertelorismhypertelorism Great variability in the severity of T cell abnormality Great variability in the severity of T cell abnormality
(<1% have thymic aplasia with absence of T cells)(<1% have thymic aplasia with absence of T cells)
Other Forms of T cell/combinedOther Forms of T cell/combined Immunodeficiency Immunodeficiency
Wiskott-Aldrich SyndromeWiskott-Aldrich Syndrome X-linked partial combined immune deficiencyX-linked partial combined immune deficiency ThrombocytopeniaThrombocytopenia, , eczemaeczema and and recurrent infectionsrecurrent infections Sinopulmonary, herpes group viruses and Sinopulmonary, herpes group viruses and
occasionally Pneumocystisoccasionally Pneumocystis Few, small platelets; elevated IgE, reduced IgMFew, small platelets; elevated IgE, reduced IgM Defect in cytoskeletal organization by WaSp (wiskott Defect in cytoskeletal organization by WaSp (wiskott
Aldrich Syndrome protein)Aldrich Syndrome protein)
X-linked lymphoproliferative disorderX-linked lymphoproliferative disorder (XLP or Duncan Disease) (XLP or Duncan Disease)
1 in 10000001 in 1000000 Avg age of onsetAvg age of onset: 2.5 yrs old, older reported: 2.5 yrs old, older reported Unique predisposition to uncontrolled infection with Unique predisposition to uncontrolled infection with Epstein Epstein
Barr virusBarr virus EBV inducesEBV induces- fatal/severe infectious mononucleosisfatal/severe infectious mononucleosis- Secondary agammaglobulinemiaSecondary agammaglobulinemia- LymphomaLymphoma- Bone marrow failureBone marrow failure Defect in SAP- loss interferes with NK and CD8+ CTL functionDefect in SAP- loss interferes with NK and CD8+ CTL function
Defects in phagocytes Defects in phagocytes generally associated with generally associated with recurrent or severe/ unusual recurrent or severe/ unusual pyogenic infectionspyogenic infections
S.aureus, Serratia, Burkholderia, Nocardia, chromobacterium, fungi (esp, S.aureus, Serratia, Burkholderia, Nocardia, chromobacterium, fungi (esp, Aspergillus)Aspergillus)
Tend to occur at interfaces between host and Tend to occur at interfaces between host and environment-skin, environment-skin, respiratory, Gl or GU tractsrespiratory, Gl or GU tracts
Failure to killFailure to kill organism results in localized infection organism results in localized infection and abscess (and abscess (CGDCGD))
Failure to mobilizeFailure to mobilize WBCs to tissues ( WBCs to tissues (LADLAD,,Chediak- Chediak- HigashiHigashi) may result in rapid spread of infection ) may result in rapid spread of infection systemicallysystemically
Defects in PhagocytesDefects in Phagocytes
Chronic Granulomatous Disease (CGD)Chronic Granulomatous Disease (CGD) ––
1: 2000001: 200000 Due to Due to genetic deficencies in NADPH oxidasegenetic deficencies in NADPH oxidase for neutrophil for neutrophil
oxidative burst required for intracellular killingoxidative burst required for intracellular killing X-linked most common X-linked most common (65-70%) also AR(65-70%) also AR Mean ageMean age of presentation 0-8 yrs,older age possible of presentation 0-8 yrs,older age possible InfectionsInfections with catalase positive organaims with catalase positive organaims (S.aureus, B.Cepacis, S.marcescens, aspergillus app.,Nocardia app)(S.aureus, B.Cepacis, S.marcescens, aspergillus app.,Nocardia app)
GranulomatousGranulomatous inflammation-lymphadenitis,osteomyelitis, inflammation-lymphadenitis,osteomyelitis,
visceral abscess, pneumoniavisceral abscess, pneumonia ProphylaxisProphylaxis with TMP-SMX,IFN- with TMP-SMX,IFN-үү,Itraconazole,Itraconazole
Defects in PhagocytesDefects in Phagocytes
Leukocyte adhesion deficiencyLeukocyte adhesion deficiency- Failure of neutrophil adhesion and migrationFailure of neutrophil adhesion and migration
to site of infection due to to site of infection due to defect in CD18 (LAD1)defect in CD18 (LAD1)- NeutrophillaNeutrophilla, recurrent life-threatening infections, little , recurrent life-threatening infections, little
inflammation at site of inlectioninflammation at site of inlection- Delayed cord separationDelayed cord separation, , severe periodontal diseasesevere periodontal disease Myeloperoxidase deficiencyMyeloperoxidase deficiency- Failure to generale hypochlorous acid in neutrophil,ARFailure to generale hypochlorous acid in neutrophil,AR- Most common Most common inherited neutrophil disorderinherited neutrophil disorder- Rarely develop serious infection-diabetics at risk for fungal Rarely develop serious infection-diabetics at risk for fungal
infectionsinfections
Defects in PhagocytesDefects in Phagocytes
Chediak-Higashi syndromeChediak-Higashi syndromeARAR, results in abnormal neutrophil granule , results in abnormal neutrophil granule formation-formation-abnormal chemotaxis abnormal chemotaxis and and degranulation degranulation with delayed killingwith delayed killingRecurrent cutaneous and respiratory infections, Recurrent cutaneous and respiratory infections, progresses to progresses to malignancymalignancy IRAK4 deficiencyIRAK4 deficiencyImportant signaling molecule in Important signaling molecule in Toll-like Toll-like receptor4 pathwayreceptor4 pathway in macrophages in macrophagesDeficiency leads to recurrent, life-threatening Deficiency leads to recurrent, life-threatening staphylococcal and pnemococcal infectionsstaphylococcal and pnemococcal infections
Defects in PhagocytesDefects in Phagocytes
Hyper-IgHyper-IgEE syndrome (Job syndrome) syndrome (Job syndrome) - - Classified as a Classified as a phagocytic disorderphagocytic disorder, but most likely , but most likely
represents represents an abnormality of T cell an abnormality of T cell function(dysregulated function(dysregulated cytokine & Igcytokine & IgEE production) production)
- - Candida infections,occult infections due to pneumocystis, Candida infections,occult infections due to pneumocystis, cryptocoocuscryptocoocus
- - Recurrent pyogenic infectionsRecurrent pyogenic infections with massively with massively elevated Igelevated IgEE levelslevels
- - Recurrent sinopulmonary infections, Recurrent sinopulmonary infections, pneumatocelespneumatoceles, , severe atopic dermatitissevere atopic dermatitis
- - S.aureusS.aureus most common pathogen most common pathogen
Defects in PhagocytesDefects in Phagocytes
Defects in complementDefects in complement system system lead to susceptibility lead to susceptibility to to encapsulatedencapsulated organisms ( organisms (S.pneumoniaeS.pneumoniae, , N.meningitidisN.meningitidis) & ) & autoimmunityautoimmunity (SLE) (SLE)
Classical pathway:Classical pathway:- Activated by IgE, IgM, CRP bound to a microbeActivated by IgE, IgM, CRP bound to a microbe MBL pathway:MBL pathway:- Activited by mannan binding lectin bound to a microbeActivited by mannan binding lectin bound to a microbe Alternative pathway:Alternative pathway:- Fluid phase activation, amplified on microbeFluid phase activation, amplified on microbe
Defects in Defects in ComplementComplement
Early classical complement deficiencies:Early classical complement deficiencies:- May be associated with May be associated with recurrent pyogenic infections recurrent pyogenic infections and or and or collagen collagen
vascular disease(SLE)vascular disease(SLE) Alternative pathway deficiencies:Alternative pathway deficiencies:- C3-C3- collagen vascular disease and significant infections with encapsulated collagen vascular disease and significant infections with encapsulated
bacteria bacteria - Properdin deficiencyProperdin deficiency-X-linked, fulminanl/ fatal infections due to a -X-linked, fulminanl/ fatal infections due to a
N.meningitidisN.meningitidis MBL deficiency:MBL deficiency:- AutoimmuneAutoimmune, worse prognosis for other infections(AIDS), , worse prognosis for other infections(AIDS),
immunosuppressed patients, liver transplantsimmunosuppressed patients, liver transplants Terminal component deficiencies:Terminal component deficiencies:
- Associated with - Associated with infections due to infections due to N.meningitidisN.meningitidis and and N.gonorrheae, chronic N.gonorrheae, chronic meningococcemlameningococcemla
Defects in ComplementDefects in Complement
Lack of synthesis:Lack of synthesis:
- - Severe liver dysfunctionSevere liver dysfunction Increased consumption:Increased consumption:
- - Immune complex mediated (SLE)Immune complex mediated (SLE)
DIC, endocarditis, disseminated gonococcal infection, DIC, endocarditis, disseminated gonococcal infection, hepatitishepatitis
- - Some glomerulonephritides- C3 nephritic factor causes Some glomerulonephritides- C3 nephritic factor causes C3 depletionC3 depletion
Loss:Loss:
- - Nephrotic syndromeNephrotic syndrome
Complement- Acquired Def.Complement- Acquired Def.
Medical historyMedical history
Physical examinationPhysical examination
Laboratory testingLaboratory testing
Diagnosis of Primary ImmunodeficiencyDiagnosis of Primary Immunodeficiency
Primary Immunodeficiency: Primary Immunodeficiency: InfectionsInfections
Birth to 3 monthsBirth to 3 months– Phagocytic cell defectsPhagocytic cell defects– Complement defectsComplement defects– DiGeorge syndromeDiGeorge syndrome
3 to 6 months3 to 6 months– Severe combined immunodeficiency (SCID)Severe combined immunodeficiency (SCID)
6 to 18 months6 to 18 months– X-linked agammaglobulinemiaX-linked agammaglobulinemia
18 months through adulthood18 months through adulthood– Common variable immunodeficiencyCommon variable immunodeficiency– Complement defectsComplement defects
Diagnosis of Primary ImmunodeficiencyDiagnosis of Primary Immunodeficiency History of SymptomsHistory of Symptoms
Growth measurementsGrowth measurements
Inspection of tonsilsInspection of tonsils
Palpation of lymph nodesPalpation of lymph nodes
OrganomegalyOrganomegaly
Skin lesionsSkin lesions
Diagnosis of Primary Immunodeficiency Diagnosis of Primary Immunodeficiency
Physical ExaminationPhysical Examination
Antibody mediated immunityAntibody mediated immunity– Quantitative immunoglobulinsQuantitative immunoglobulins– IgG subclass determinationIgG subclass determination– IsohemagglutininsIsohemagglutinins
T-cell immunityT-cell immunity– Total lymphocyte countTotal lymphocyte count– Lateral chest x-ray (infants)Lateral chest x-ray (infants)– Delayed hypersensitivity skin Delayed hypersensitivity skin
tests (individuals >2 years of tests (individuals >2 years of age)age)
Diagnosis of Primary Immunodeficiency Diagnosis of Primary Immunodeficiency
Screening TestsScreening Tests
NeutrophilNeutrophil– White blood cell count and White blood cell count and
differentialdifferential ComplementComplement
– Total hemolytic complement Total hemolytic complement test (CH50)test (CH50)
– C3 and C4 concentrationC3 and C4 concentration
Diagnosis of Primary ImmunodeficiencyDiagnosis of Primary Immunodeficiency
Screening TestsScreening Tests
Advanced TestsAdvanced Tests
Diagnosis of Primary ImmunodeficiencyDiagnosis of Primary Immunodeficiency
Management of PIDManagement of PID
General treatmentGeneral treatment
Replacement therapyReplacement therapy
Immune reconstructionImmune reconstruction
Gene therapyGene therapy
General Management of PIDGeneral Management of PID DietDiet Avoidance of pathogens Avoidance of pathogens (“germ-free” care)(“germ-free” care) AntibioticsAntibiotics
- use in acute illness- use in acute illness
- Prophylactic- Prophylactic Avoid whole blood Avoid whole blood transfusion in combined transfusion in combined
immunodeficiency disorder (GVHR)immunodeficiency disorder (GVHR) Avoid live virus Avoid live virus vaccines and BCGvaccines and BCG
Immunoglobulin replacementImmunoglobulin replacement
Treatment of severe antibody disordersTreatment of severe antibody disorders
IVIG 400~ 600 mg/kg/m iv dripIVIG 400~ 600 mg/kg/m iv drip
SCIGSCIG
Frozen plasma 10ml/kg/monthFrozen plasma 10ml/kg/month
CautionCaution : :
with administration of blood productswith administration of blood products if if
selective IgA deficiencyselective IgA deficiency
Specific treatment for cellular deficiencySpecific treatment for cellular deficiency Bone marrow transplantationBone marrow transplantation
Replacement therapyReplacement therapy
- Enzyme replacement- Enzyme replacement
- Gene therapy- Gene therapy
- Thymic hormones- Thymic hormones
- Cytokines- Cytokines
Fetal thymus transplantationFetal thymus transplantation
Interferon gammaInterferon gamma for CGD for CGD
Granulocyte transfusionGranulocyte transfusion
THANKS
متشكرم