Morning ConferenceJuly 22, 2009
Araya Tangwitoon, MD
HistoryHistory
•• A 14A 14--yearyear--old girl old girl presented with chronic presented with chronic
rhinosinusitisrhinosinusitis and recurrent and recurrent otitisotitis media. media.
•• She had a She had a history of recurrent history of recurrent otitisotitis media since media since
88--yryr--old & a history of recurrent old & a history of recurrent rhinosinusitisrhinosinusitis since since
1010--yryr--old, which not respondedold, which not responded to treatment with to treatment with
various antibioticsvarious antibiotics..
• Nasal discharge culture (1st): P. aeruginosaSensitivity to ciprofloxacin
• Nasal discharge culture (2nd): M. morganiiSensitivity to amikacin, ceftazidime, cefoxitin, imipenem
•• CBC: CBC: HbHb 12.8 mg/12.8 mg/dLdL HctHct 39.2% 39.2%
WBC 8100 /mmWBC 8100 /mm33 N 67% L 26% M 4% Eo1.4%N 67% L 26% M 4% Eo1.4%
PltPlt 216,000 /mm216,000 /mm33
•• Serum Serum IgGIgG 12.4 mg/12.4 mg/dLdL (600(600--1600)1600)
IgMIgM <18.6 mg/<18.6 mg/dLdL (40(40--160)160)
IgAIgA <5.91 mg/<5.91 mg/dLdL (80(80--480)480)
Problem ListsProblem Lists
• A 14-yr-old girl with CRS
• Recurrent sinopulmonary tract infections
• Panhypogammaglobulinemia
•• Secondary Secondary hypogammaglobulinemiahypogammaglobulinemia
•• Primary ImmunodeficiencyPrimary Immunodeficiency
Physical ExaminationPhysical Examination
•• A Thai girl, good consciousness, well coA Thai girl, good consciousness, well co--operateoperate
•• BW 48 kg (P50BW 48 kg (P50--75), Ht 158 cm (P5075), Ht 158 cm (P50--75)75)
•• HEENT: not pale, no jaundiceHEENT: not pale, no jaundice
RtRt ear: TM perforation with opacity & ear: TM perforation with opacity & mucoidmucoid
dischargedischarge
Nose: purulent discharge both nostrils, Nose: purulent discharge both nostrils, Inferior turbinate 3+ bothInferior turbinate 3+ both
Tonsils: 1+, Tonsils: 1+, mucopurulentmucopurulent postnasal drippostnasal drip
•• Heart: normal S1S2, no murmurHeart: normal S1S2, no murmur
•• Lungs: Clear, Lungs: Clear, RtRt = Lt= Lt
•• AbdAbd: soft, not tender, spleen: just palpable, : soft, not tender, spleen: just palpable,
no no hepatomegalyhepatomegaly
•• Ext: normalExt: normal
•• Flow Flow cytometrycytometry: :
WBC 9,050/ul WBC 9,050/ul
Absolute total lymphocyte 2,054/ulAbsolute total lymphocyte 2,054/ul
Lymphocyte 22.7%Lymphocyte 22.7%
%CD3%CD3 92%92% Absolute CD3 1,890 /Absolute CD3 1,890 /ulul
%CD4%CD4 55%55% Absolute CD4 1,130 /Absolute CD4 1,130 /ulul
%CD8%CD8 34%34% Absolute CD8 698 /Absolute CD8 698 /ulul
%CD19%CD19 2%2%
%CD56%CD56 6%6%
•• Serum Serum IgGIgG < 7.3 mg/< 7.3 mg/dLdL (600(600--1600)1600)
IgMIgM < 18.6 mg/< 18.6 mg/dLdL (40(40--160)160)
IgAIgA < 5.91 mg/< 5.91 mg/dLdL (80(80--480)480)
•• Flow Flow cytometrycytometry: WBC 6,150: WBC 6,150 //ulul
ALC 1,550/ul ALC 1,550/ul Lymphocyte 25.2%Lymphocyte 25.2%
%CD3%CD3 91%91% Absolute CD3 1,411 /Absolute CD3 1,411 /ulul
%CD4%CD4 54%54% Absolute CD4 837 /Absolute CD4 837 /ulul
%CD8%CD8 34%34% Absolute CD8 527 /Absolute CD8 527 /ulul
%CD19%CD19 1%1%
%CD56%CD56 5%5%
Problem ListsProblem Lists
• A 14-yr-old girl with CRS
• Recurrent sinopulmonary tract infections
• Panhypogammaglobulinemia
• Low number of circulating B cell
•• Secondary Secondary hypogammaglobulinemiahypogammaglobulinemia
•• Primary ImmunodeficiencyPrimary Immunodeficiency
–– AutosomalAutosomal AgammaglobulinemiaAgammaglobulinemia
–– XX--Linked Linked AgammaglobulinemiaAgammaglobulinemia
–– Common Variable ImmunodeficiencyCommon Variable Immunodeficiency
Secondary hypogammaglobulinemia
• Drug-induced
– Anticonvulsants (e.g., carpamazepineand phenytoin)
– Gold salts
– Penicillamine
– Antimalarial agents
– Methotrexate
• Excessive loss of immunoglobulins
– Protein-losing enteropathy
– Nephrotic range proteinuria
– Severe burns
• Malignancy
– Chronic lymphocytic leukemia
– Non-Hodgkin's B-cell lymphoma
• Infectious diseases
– Epstein-Barr virus
XLA or AR Agammaglobulinemia CVID
Age at onset XLA: 6-12 monthsAR: younger than XLA
Any ages; peak in first & third decades
Sex XLA: malesAR: males and females
males and females
Clinical manifestations
recurrent infections; more severe in AR agammaglobulinemia
recurrent infections,autoimmune manifestations,lymphoma & other selected cancers.
Lymphoid tissue hypoplasia or absent Normal-sized or Enlarged
profound hypogammaglobulinemia(IgG, IgA and IgM)
Peipheral B Cells almost complete absence ofperipheral B cells, as defined byCD19 & CD20 expression (<2%)
normal or low number
XLA; BTK mutationAR; μ heavy chain, Igα, Igß,
λ5/VpreB, BLNK
Serum Ig level Decreased IgG, IgAand/or IgM
Molecular analysis ICOS, CD19, TACI, BAFF-R, Msh5
XLA
AR Agammaglobulinemia
CVID
Berek C et al. Clinical Immunology Principles and Practice.3rd Edition.
Autosomal Recessive Agammaglobulinemia
• When compared with XLA
– an earlier onset of disease
– more severe complications
• Females with early onsetinfections, profoundhypogammaglobulinemia andabsent B cells
• Male patients with negative BTKmutation analysis results
Schroeder HW Jr. Clinical Immunology Principles and Practice.3rd Edition.Aghamohammadi A et al. Primary Immunodeficiency Diseases: Definition, Diagnosis, and Management 1st edition.
S Ferrari et al.Genes and Immunity 2007;8:325–33.
•• 4 pts: homozygous 4 pts: homozygous mutation in IGHMmutation in IGHM
•• 2 pts: 2 pts: compoundcompoundheterozygousheterozygous variationsvariationsinin VpreBVpreB11 genegene
•• SeveralSeveral newnew singlesinglenucleotidenucleotidepolymorphismspolymorphisms bothboth ininthethe μμHCHC andand inin thethe λλ55--likelike//VpreBVpreB--codingcoding genesgeneswerewere identifiedidentified..
Clinical findings in AR agammaglobulinemia
Lopez-Granados E, Porpiglia A, Hogan MB, et al. J Clin Invest 2002; 110:1029-35.
• A 10-month-old Japanese girl with frequent respiratory infectionsand otitis media (onset of infections: 8-month-old)
• Her father was diagnosed as having XLA.
• Her serum IgG 6 mg/dL, IgA 1 mg/dL, IgM 5 mg/dL
• Flow cytometric analysis
– the lack of peripheral B cells with the block of B-cell differentiation in the stages between pro-B cells and pre-B cells in the bone marrow
– the defect of the Bruton tyrosine kinase (BTK) expression on monocytes
Takada H et al. Blood. 2004;103:185-187.
Defect of BTK and block of B-cell differentiation.
Takada H et al. Blood. 2004;103:185-187
PatientPatient Healthy Healthy controlcontrol
PatientPatient Healthy controlHealthy control
PtPt MotherMother FatherFather
Paternal Paternal Grand Grand mommom BrotherBrother
• Maternally derived X chromosome was exclusively inactivated in peripheral blood & oral mucosal cells.
Takada H et al. Blood 2004;103:185-187.
XLA
(Heterozygous abnormality of the BTK gene &
nonrandom X inactivation of maternally derived X chromosome in which normal
BTK gene is located.)
Problem ListsProblem Lists
• A 14-yr-old girl with CRS
• Recurrent sinopulmonary tract infections
• Panhypogammaglobulinemia
• Low number of circulating B cell
•• Secondary Secondary hypogammaglobulinemiahypogammaglobulinemia
•• Primary ImmunodeficiencyPrimary Immunodeficiency
–– AutosomalAutosomal AgammaglobulinemiaAgammaglobulinemia
–– XX--Linked Linked AgammaglobulinemiaAgammaglobulinemia
–– Common Variable ImmunodeficiencyCommon Variable Immunodeficiency
Physical ExaminationPhysical Examination
•• A Thai girl, good consciousness, well coA Thai girl, good consciousness, well co--operateoperate
•• BW 48 kg (P50BW 48 kg (P50--75), Ht 158 cm (P5075), Ht 158 cm (P50--75)75)
•• HEENT: not pale, no jaundiceHEENT: not pale, no jaundice
RtRt ear: TM perforation with opacity & ear: TM perforation with opacity & mucoidmucoid
dischargedischarge
Nose: purulent discharge both nostrils, Nose: purulent discharge both nostrils, Inferior turbinate 3+ bothInferior turbinate 3+ both
Tonsils: 1+,Tonsils: 1+, mucopurulentmucopurulent postnasal drippostnasal drip
•• Heart: normal S1S2, no murmurHeart: normal S1S2, no murmur
•• Lungs: Clear, Lungs: Clear, RtRt = Lt= Lt
•• AbdAbd: soft, not tender, : soft, not tender, spleen: just palpablespleen: just palpable, ,
no no hepatomegalyhepatomegaly
•• Ext: normalExt: normal
Common Variable Immunodeficiency
CVIDCVID• The most common symptomatic PID
• A group of genetically, immunologically &
clinically heterogeneous disorders
• Hypogammaglobulinemia & recurrent
infections
• Complicated by autoimmunity,
granulomatous inflammation,
lymphoproliferation & malignancy
• Inherited in 10-20% of patients
• Associated genetic defects: ICOS, TACI,
CD19, BAFF-R and Msh-5
CVID: CVID: DefinitionDefinition
• Hypogammaglobulinaemia of
> 2 immunoglobulin isotypes
(significant reduction of IgG (>2SD),
reduction of IgA or IgM)
• Recurrent infections
• Impaired functional antibody responses
• Exclusion of other primary antibody
deficiency syndromes & secondary
causes of hypogammaglobulinemia
www.ESID.org
Clinical Features of
CVID patients
CVID: Age at onset & diagnosisNo. of CVID
patients
Age at evaluation; year
Age at onset; year
Age at Diagnosis; year
Delay Diagnosis;
year
Chapel H et al. Blood 2008;112:277-86.
334 mean±SD: 49.4±16.3
(11-90)
mean±SD:
47±17
(10-84)
Median: 44
(12-87)
< 18
Llobet et al.
Pediatr Allergy Immunol2009: 20: 113–118.
22 < 18 NA Median: 7.8
(2.5-16)
NA
Mean: 26.3 median: 24
Mean: 33.5 median: 33
NA
Wehr C et al.
Blood 2008;111:77-85.
303 mean±SD: 27±17
mean±SD:
35±16
NA
Oksenhendler E et al.
Clinical InfectiousDiseases2008;46:1547–54
252 Median: 19 Median: 33.9 Median: 6.9
(0-55)
URSCHEL S et al. J Pediatr 2009;154:
888-94.
32 NA Median:
10.4±4.3
(1.1-17.4)
Median:
5.8±4.2
(0.2-14.3)
Park MA et al. Lancet 2008;372:489-502.
Infectious complications
in CVID patients
Oksenhendler E et al. Clinical Infectious Diseases 2008;46:1547–54.
Chapel H and Cunningham-Rundles C. British Journal of Haematology 2009;145:709–727.
(originally published in Blood. Chapel H. et al. Blood 2008;112:277–286.)
Chapel H et al. Blood 2008;112: 277-86.
a noninfectious complication (with or without breakthrough infections).only breakthroughinfections
Lymphocytic infiltration: n=38Autoimmunity: n=72Enteropathy: n=7Malignancy: n=1
lymphocytic infiltration+autoimmunity: n=28Enteropathy+lymphocytic infiltration: n=8lymphocytic infiltration+malignancy: n=1Enteropathy+autoimmunity: n=3Autoimmunity+malignancy: n=2
Autoimmunity+lymphocytic infiltration+enteropathy: n=9Autoimmunity+lymphocytic infiltration+malignancy: n=4Lymphocytic infiltration+enteropathy+malignancy: n=1
autoimmunity,lymphocytic infiltration,enteropathy,malignancy: n=1
Chapel H et al. Blood 2008;112: 277-86.
Disease complication prevalences
WEHR et al.(Blood 2008; 111:77-85.)
CHAPEL et al(Blood. 2008;112:277-86.)
No. of CVID patients 303 334
Splenomegaly, % 40.5 30
Lymphadenopathy, % 26.2 15
Granulomatous disease, % 11.6 8
Autoimmune phenomena*, % 20.3 25
Autoimmune cytopenia, % 20.2 12
*not include autoimmune *not include autoimmune cytopeniacytopenia
Wehr C et al. Blood 2008;111:77-85.
Chapel H et al. Blood 2008;112: 277-86.
URSCHEL S et al. J Pediatr 2009;154:888-94.
Immunological analysis of
CVID patients
Serum
Immunoglobulin
at diagnosis
Chapel H and Cunningham-Rundles C.British Journal of Haematology 2009;145:709–727.
European cohort
United States Cohort
Serum IgG < 1 g/L
Serum IgG 1.1-3 g/L
Serum IgG >3, <6.5 g/L
URSCHEL S et al. J Pediatr 2009;154:888-94.
Pediatric population diagnosed of CVID
Serum level in each patient at first diagnosis
IgG
IgM
IgA
Peripheral B Cells
Chapel H et al. Blood 2008;112: 277-286.
NNo o significantsignificant associationsassociations withwith clinicalclinical phenotypesphenotypes
Wehr C et al. Blood 2008;111:77-85.
Association of clinical phenomena with dysregulated B-cell subpopulations.
Llobet et al. Pediatr Allergy Immunol 2009: 20: 113–118.
Pediatric population diagnosed of CVID
URSCHEL S et al. J Pediatr 2009;154:888-94.
Classification systems for CVID
Peripheral blood B-cell subsets
Park MA et al. Lancet 2008;372:489-502.
Expert Review of Clinical Immunology 2009.
Classification
systems
for
CVID
Evaluation of the Paris and Freiburg classification scheme.
Wehr C et al. Blood 2008;111:77-85.
P = 0.03
P = 0.02
P = 0.04
P < 0.001
P = 0.02
Wehr C et al. Blood 2008;111:77-85.
P < 0.001
P < 0.01
P = 0.002
P = 0.009
P = 0.049
P = 0.03
P = 0.016
P < 0.001
Genetics of CVID
Genetics for CVIDGenetics for CVID
• ICOS
• CD19
• TACI (TNFRSF13B)
• BAFF-R (TNFRSF13C)
• Msh5
The inducibleinducible costimulator (ICOS) gene
Park MA et al. Lancet 2008;372:489-502.
• Germinal center formation • Memory B cell development• Provide T-cell dependent antibody response for B cell
Fig. 1. Inducible co-stimulator molecule (ICOS) : ICOS-L signalling can results in multiple pathways.
C. Bacchelli et al. Clinical and Experimental Immunology 2007;149: 401–9.
ICOS DeficiencyICOS Deficiency
• About 2% of patients with CVID
• Inherited as autosomal recessive trait
• 9 CVID patients from 4 apparently unrelatedfamilies descended from a common founder
• Geographical location: along the river Danube
• Serum IgG & IgA levels were markedlyreduced in all patients
– IgG < 1.9-2.55 g/L
– IgA < 0.06-0.58 g/L
• Serum IgM level
– reduced in 6/9 patients
– low normal values in 3/9 patients
C. Bacchelli et al. Clinical and Experimental Immunology 2007, 149: 401–409.
Yong et al. Immunological Reviews 2009;229: 101–113.Park MA et al. Lancet 2008;372:489-502.
• Marked impairment of germinal center formation
• The clinical phenotype shows nearly all complication
(autoimmunity, benign lymphoproliferation, chronic
granulomatous inflammation & malignancy).
C. Bacchelli et al. Clinical and Experimental Immunology 2007;149: 401–409.Yong et al. Immunological Reviews 2009;229: 101–113.
• Circulating B cells
– Markedly reduced in 5/9 patients
– Slightly elevated in 2/9 patients
• Switched memory B cells: absent in all patients
• Few abnormalities in T-cell phenotype & function
– 3 patients had an inverted CD4⁄CD8 ratio.
– Normal in vitro proliferation responses when stimulated with
mitogens & antigens
Yong et al. Immunological Reviews 2009;229: 101–113.
The B cell receptor signaling complex
Park MA et al. Lancet 2008;372:489-502Schaffer AA et al. Current Opinion in Genetics & Development 2007, 17:201–12.
CD19 Deficiency•• 44 patients patients with with homozygoushomozygous mutationsmutations inin thethe CDCD1919 genegene,,
fromfrom 22 unrelatedunrelated familiesfamilies
–– increasedincreased susceptibilitysusceptibility toto infectioninfection
–– hypogammaglobulinemiahypogammaglobulinemia
–– normalnormal numbersnumbers ofof CD20+CD20+ B B cellscells
–– expressionexpression ofof CDCD 1919 onon B B cellscells
•• unundetectabledetectable in 1/4 patientsin 1/4 patients
•• barelybarely detectabledetectable in 3/4 patientsin 3/4 patients
van Zelm MC, Reisli I, van der Burg M et al. N Engl J Med 2006;354:1901-12.
•• Numbers of CD27+ memory B cells & CD5+ B cellsNumbers of CD27+ memory B cells & CD5+ B cells
•• Normal germinal center formationNormal germinal center formation
•• Poor antibody response to rabies vaccinationPoor antibody response to rabies vaccination
•• NNo o autoimmuneautoimmune featuresfeatures oror signssigns ofof lymphoproliferationlymphoproliferation
van Zelm MC, Reisli I, van der Burg M et al. N Engl J Med 2006;354:1901-12.
Park MA et al. Lancet 2008;372:489-502
The APRIL–BAFF network
InteractionsInteractions ofof BBAFF, APRIL with AFF, APRIL with theirtheir receptorsreceptors
C. Bacchelli et al. Clinical and Experimental Immunology 2007;149: 401–9.
• Prevalence: 10-20% of CVID patients
• Risk factors, not solely disease-causing in CVID
• Associated with
– Lymphoproliferation
• splenomegaly
• tonsillar hyperplasia
• follicular nodular hyperplasia of GI
– Autoimmunity
• hemolytic anaemia
• autoimmune thrombocytopaenia
• thyroiditis
TACI MutationTACI Mutation
Park MA et al. Lancet 2008;372:489-502.Young PFK et al. Immunol Allergy Clin N Am 2008;28:367-86.
C. Bacchelli et al. Clinical and Experimental Immunology 2007;149: 401–409.
• A multicenter study involving 564 unrelatedCVID patients
• 8.8% (50/564) of the patients carriedat least 1 mutated TACI allele.
– 4% (2/50): homozygous mutations
– 14% (7/50): compound heterozygous mutations
– 82% (41/50): heterozygous mutations
Salzer U et al. Blood 2009;113:1967-76.
TACI MutationTACI Mutation
•• TACITACI C104C104RR && A181EA181E
–– mutationalmutational ''hotspotshotspots‘‘
–– ApproximatelyApproximately 80%80% ofof thethe sequencesequence variantsvariants inin TACITACI
–– presentpresent inin a a heterozygousheterozygous statestate inin 2% 2% ofof 675675 healthy healthy
controlscontrols
Salzer U et al. Blood 2009;113:1967-76.
Salzer U et al. Blood 2009;113:1967-76.
Zhang et al. 2007
• 7.3% (13/176) of subjects had HeterozygousTACI mutations.
• Autoimmune thrombocytopenia
– 46% of subjects with mutations
– 12% of subjects without mutations
• Mutations in TACI significantly predispose toautoimmunity and lymphoid hyperplasia in CVID.
• Splenomegaly and splenectomy weresignificantly increased (P 5 .012; P 5 .001).
• 8 first-degree relatives from 5 families had thesame mutations but were not immune-deficient.
Zhang et al. J Allergy Clin Immunol 2007;120:1178-85
Zhang et al. J Allergy Clin Immunol 2007;120:1178-85.
Immunologicphenotype of
TACI-deficientpatients.
Salzer U et al. Blood 2009;113:1967-76.
Autoimmunity &lymphoproliferationin TACI deficiency
Salzer U et al. Blood 2009;113:1967-76.
36% (18/50)
60% (30/50)
BAFFBAFF--R R DeficiencyDeficiency
• Described in only 1 patient
• a 60-year-old male with
hypogammaglobulinaemia
• Profound reduction of both class switch
(CD27+, IgM-, IgD-) & non-switched memory
(CD27+, IgM+, IgD+)
• Transitional B cell (CD38+++, IgM++)
• Plasmablasts (CD38+++, IgM-)
Park MA et al. Lancet 2008;372:489-502.C. Bacchelli et al. Clinical and Experimental Immunology 2007;149: 401–409.
MutSMutS 5 5 ((MMshsh55))
• A gene encoded in the central
MHC class III region
• A critical role in regulating meiotic
homologous recombination
• A role in class switch recombination
• Msh5 Mutation: associated with CVID
and selective IgA deficiency.
Sekine et al. Proc Natl Acad Sci U S A. 2007 ;104(17):7193-8.Young PFK et al. Immunol Allergy Clin N Am 2008;28:367-86.
Gene (chromosomal
location)
Frequency (%) Inheritance Phenotype B-cell phenotype Clinical phenotype
ICOS (2q33) 2
8-20
1
< 1
CVID Low numbers ofB-cell & memory B cells
Recurrent respiratoryinfections,autoimmunity,granulomata andmalignancy
AR
TNFRSF13B/ TACI
(17p11.2)
AD • CVID, • IgGsubclass deficiency• sIgAD
No specific B-cellphenotype
Recurrent respiratoryinfections, increasedrates of benignlymphoproliferation andincreased rates ofautoimmunity
ARCD19(16p11.2)
CVID Decrease in classswitched memory B cells, low CD21expression on B cells, normalnumbers of CD20+mature B cells inperipheral blood
Recurrent respiratoryinfections
TNFRSF13C/ BAFF-R
(22q13.1-q13.31)
AR CVID Low B-cell numbers,relative increase intransitional B cellsand low numbersof memory B cells
Recurrent respiratoryinfections
Expert Review of Clinical Immunology, March 2009, Vol. 5, No. 2, Pages 167-180 al. Lancet 2008;372:489-502.Park MA et
TherapeuticTherapeutic ManagementManagement
• Prevention of recurrent and chronic
infections by Immunoglobulin therapy
• Antibiotic therapy of breakthrough
infections
• Treatment of associated disease
complications and sequelae
Common Variable Immunodeficiency
• A 14-yr-old girl with CRS
• Recurrent sinopulmonary tract infections
• Panhypogammaglobulinemia
• Low number of circulating B cell
• Splenomegaly
Management
• Treatment of infections
• Intravenous immunoglobulin
replacement therapy
• Genetic Testing
• Surveillance for autoimmunity and
malignancy
……THANK YOUTHANK YOU……
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