Common variable immunodeficiency
•Descargar como PPTX, PDF•
15 recomendaciones•4,583 vistas
Common variable immunodeficiency, Presented by Sasikarn Suesirisawad, MD
![DEfinition ,[object Object]](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
Recomendados
Más contenido relacionado
La actualidad más candente
La actualidad más candente (20)
Destacado
Destacado (20)
Similar a Common variable immunodeficiency
Similar a Common variable immunodeficiency (20)
Más de Chulalongkorn Allergy and Clinical Immunology Research Group
Más de Chulalongkorn Allergy and Clinical Immunology Research Group (20)
Último
Último (20)
Common variable immunodeficiency
- 1. Common variable immunodeficiency Sasikarn Suesirisawad, MD
- 4. Impaired functional antibody responses
- 6. Poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines(S. pneumoniae)
- 11. Flow cytometry B cell subpopulation
- 12. Association of clinical phenomena with dysregulated B cell subpopulations
- 13. Evaluation of the Paris and Freiburg classification scheme. P<0.001 P=0.03 P=0.04 P=0.02 P=0.02
- 15. P=0.03 P=0.009 P<0.01 P=0.049 P=0.016
- 18. Low CD4/CD8 T cell ratio due to decrease in CD4 or increase CD8
- 19. Reduced T regulatory cells
- 22. 25 % of all CVID pts present in childhood or adolescence, earlier peak of diagnosis at 8 yrs of age. An Pediatr (Barc). 2011;74(2):74. J Pediatr. 2009;154(6):888.
- 24. Median age of first symptom was 19 yr Median age at CVID diagnosis was 33.9 yr
- 25. Delay between first symptom and diagnosis of CVID
- 31. Coincidence of granulomatous disease and autoimmmune cytopenia with splenomegaly in CVID
- 33. Mary Lucas et al. JACI 2010
- 38. Ann Allergy Asthma Immunol. 2006;97(5):653
- 42. 83 % had asthma.
- 48. GI infections: H. pylori and Giardia lamblia. Salmonella, Shigella, Campylobacter.
- 49. Ann Intern Med. 1993;118(9):720
- 50. Crohn's disease and ulcerative colitis
- 52. Nodular intestinal hyperplasia occurs relatively frequently in adolescents with CVID
- 56. a b c d e f g h
- 58. Autoimmune cytopeniasare more common presenting disorder in children than adults.
- 59. Autoimmune neutropenia, thrombocytopenia, hemolytic anemia
- 62. The most frequently diagnosed disorder is B cell lymphoma Am J Hematol. 2002;69(3):171.
- 65. Enteroviralinfection has not described in pediatric CVID.
- 66. In contrast, neurodegenerative diseases described in other pediatric immunodeficiencies (esp. X-linked agammaglobulinemia)Brain. 1996;119 ( Pt 1):1. Ann Allergy Asthma Immunol. 2007;98(5):483
- 67. BAFF-R TACI
- 71. Serum IgG and IgA levels were markedly reduced in all patients
- 72. IgG<1.9-2.55 g/L
- 73. IgA<0.06-0.58g/L
- 74. Serum IgMlevel
- 75. reduced in 6/9 patients
- 76. low normal values in 3/9 patientsC.Bacchellietal.ClinicalandExperimentalImmunology2007, 149:401–409. Yongetal.ImmunologicalReviews2009;229:101–113.Park MA et al. Lancet 2008;372:489-502
- 80. Associated with
- 82. splenomegaly
- 84. follicular nodular hyperplasia of GI
- 85. Autoimmunity
- 88. thyroiditisTACI MutationTACI MutationPark MA et al. Lancet 2008;372:489-502. Young PFK et al. ImmunolAllergy ClinN Am 2008;28:367-86. C.Bacchellietal.ClinicalandExperimentalImmunology2007;149:401–409.
- 90. 60-year-old male with hypogammaglobulinaemia
- 91. Profound reduction of both class switch (CD27+, IgM-, IgD-) and non-switched memory (CD27+, IgM+, IgD+) Transitional B cell (CD38+++, IgM++) Plasmablasts(CD38+++, IgM-)Park MA et al. Lancet 2008;372:489-502. C.Bacchellietal.ClinicalandExperimentalImmunology2007;149:401–409.
- 93. A critical role in regulating meiotic homologous recombination
- 94. A role in class switch recombination
- 98. MANAGEMENT
- 106. CVID and fever should be evaluated promptly. identify organisms such as rapid viral identification kits for influenza or RSV.
- 108. HRCT of chest may be of value in detecting early and progressive pulmonary structural damage
- 110. Killed viral and bacterial vaccines: hope that generate T cell-mediated immune responses that may afford some additional protection beyond that obtained with Igreplacement therapy.
- 111. Many children will retain ability to mount responses to some polysaccharide Ag, while they are non-responsive to others.
- 112. Immunization against transmissible infectious agents is encouraged for close family members.
- 114. Prognosis is good.
- 115. Death during childhood from complications of CVID is extremely rare once immune globulin therapy is instituted.
- 119. Thank you
Notas del editor
- Criteria for possible or probable CVID diagnosis established by international concensus statement
- B cell develop in BM from hematopoietic stem cell through rearrangement of Ig heavy chain and light chain and initial selection of repertoire with selection against autoreactive B cell.Mature B cell express both IgM and IgD export from BM and enter secondary lymphoid organAffinity maturation take place through somatic hypermutation of variable region gene in germinal center of secondary lymphoid follicle where isotype class switching take place, enable production of IgG IgA IgE B cell selected through affinity maturation become memory B cell or long lived plasma cell that home back to BM and produce high-affinity Ab.
- CD19 :pan B cell marker CD27: memory phenotype and presence or absence of IgM and IgDCD38 and IgM distinguish transitional B cell and plasmablastCD21: marker for B cell activation and expressed on mature B cell
- Flow cytometryPBMC gating on lymphocyteB cell marker CD191)Naive IgD+ IgM+ CD27- Bcell2)Marginal zone B cell: IgD+ IgM+CD27+:less effect3)Switch memory B cell: IgD- IgM-CD27+: ลดลง4)CD38 low CD21low:found in auto5)CD38++IgMhi transitional B cell6)CD38+++IgM- plasmablast: reduce in CVID
- The most significant dysregulation of B cell subpopulation Pt with splenomegaly: tend to lower % B cell, MZ B cell, switch memory B cellBest marker for splenomegaly is increase CD21 low B cell(b) Lymphadenopathy: asso increase transitional B cellGranulomatous disease: connected with severe reduction of switch memory B cell
- Comparison of scheme: 303ptParis: reduction of both CD27+ b cell < 11% (MB0) = 48% at least of swicth memory B cell (MB1) = 43 % nearly normal CD27+ B cell (MB2) = 9% significant increase splenomegaly in gr MB0(47%) compare with MB2(23%) granulomatous dZ more common in MB0 than MB1 absent in MB2Freiburg: gr1(77%) ↑ CD21 low=gr1a gr 2 (23%) splenomegaly significant increase in gr1a compare with gr1b granulomatous Dz common in gr1a 20% than gr2
- ≤1% B cell (gr B-)>1% B cell (gr B+) B+ แบ่งเป็น smB - ≤2% switched memory B cell smB + >2% switch memory B cellSevere reduction of class switched B cell asso with significant decrease serum IgGsplenomegaly and granulomatous dz increase in smB –smB-Trhi≥ 9% transitional B cell: lymphadenopathy
- Expansion of CD21low B cell above 10% of B cell designated 21loExpansion of CD21low B cell significant more common in gr smB- than gr smB+Incidence of splenomegaly increase in smB-21low compare with CD21norGranulomatous dZ common in smB-21low, absent in smB+21norsmB+21lo more common c splenomegaly than smB+21 norGranulomatous dZ common in smB21 lo, nearly absent in smB+21nor
- PID tertiary paediatric centre in South Africa.retrospective study: 16 pts diagnosed with PID from 1983 - 2009.Results: Ab deficiencies predominated(51%) followed by well-defined syndromes(24%). Common variable immunodeficiency was commonest antibody deficiency.mean age of diagnosis was 51 mo overall but decreased significantly to 35 mo over the last 9 yrs.
- Prospective enroll adult pt 2004-2007 with PID ,341 enroll 252 is CVIDMedian age of first symptom was 19 yrMedian age at CVID dx was 33.9 yr
- Median delay of Dx was 6.9 yr(0-55 yr)15.6 yr for 138 pt whom initial symptom before 19902.9 yr for 114 pt whom initial symptom after 1990Median delay of Dx was 14 yr: pt whom initial symptom before 15 yr 3.7 yr: pt whom initial symptom after 15 yr
- IgG: circle, IgM:triangle, IgA:diamondUpper chart: line 3 percentile of normal IgGLower chart: : line 3 percentile of IgM and IgA
- Lymphocyte subset distribution in CVID at first diagnosis.Normal percent for CD4+T cell, CD8+T cell, NK cellB cell within lower normal range
- Lt: healthy organRt: organ system involvement. Pt also have increased risk of neoplasia, RA, vitiligo, autoimmune disease
- French national study prospective enroll 2004-2007, 341 enrolled, 252 dx CVIDMost frequent initial symtom were URI: bronchitis, sinusitis, pneumonia and/or bronchiectasis
- Respiratory tract is most common involved 73% of pt attributable to S.pneumonia, H.influenza, mycoplasmaSevere bacterial infection such as empyema, sepsis, meningitis,osteomyelitis, often same orgainism, are less common.Current cohort , 90% of 476 had ≥ 1 infectious complication
- European cohort 303 CVID demonstrate strong association among granulomatous inflammation, autoimmune phenomena and splenomegalyGranulomatous disease is almost exclusively detected in pt with splenomegaly(28/33 pt, P < 0.001)Autoimmune cytopenia, other autoimmune phenomena, lymphadenopathy significant associated with splenomegalySignificant coincidence of autoimmunity and other autoimmune phenomena with granulomatous disease3 pt, granulomatous disease and autoimmune cytopenia in absent of splenomegaly
- 240 pt had RS symptom, pneumonia report in 147 pt:S. pneumoniae, H. influenzae document in 46 and 17 caseRecurrent and chronic diarrhea report in 118 pt: giardia =35, salmonella=19,campylobacter=19
- Prospective cohort 90 pt confirmed CVID Oxford UK LA follow up 22 yrNumber type and severity of infection in CVID , red bar are propation of infection type that classified as severe
- Before Dx CVID chronic or recurrent infection present in majority of Pt. Most pt affected with infection of upper and lower RS tract.
- Lymphocytic pulmonary infiltrationA: 40 yr woman gradually worsening severe lung disease. CT chest revealed massive infiltrative composed of lymphocytic collection and fibrotic scarB: biopsy, infiltration T cell in lung, obliterating normal architecture.
- 62 CVID perform SPT , specific IgE for aeroallergen and bronchial provocation with histamine and allergen.
- Most common was obstructive lung disease in 29(47.5%) of 62 pt.18(29%) of 62 pt clinical suggest allergic asthma
- Asthma diagnosed in 9 (14.5%)pt and atopy had 6, allergic ashma diagnosed in 4 pt.CVID testing negative for specific IgE Ab and suspected allergic asthma presented positive response to bronchial provocation test with allergen.
- Autoimmune disease up to 25%, mostlyITP, AIHA or evan syndrome, autoimmune neutropenia
- Incidence of malignancy 15% of subject. 5 fold increase in cancer, excess of stomach cancer (47 fold), NHL (30 fold)Cohort of 476 pt, 3 stomach cancer(0.6%), 32 NHL(6.7%) and 4 case of HD
- Genetic defect in CVID, defect in 4 geneICOS( inducible T cell costimulator)Deficiency of ICOS expressed on T cell9 pt c mutation in ICOS present with recurrent bacterial infection, splenomegaly, autoimmune neutropenia, intestinal lymphoidhyperlasia, neoplasiaLow peripheral B cellFew/no class switched B cell, hypogammaglobulinemiaT cell from ICOS deficient produce very little IL10, asso defective formation of germinal center leading to impaire B cell memoryARICOS upregulate on both CD4 and CD8 effector and memory T cell and activated NK cell & enhance NK cell functionICOS express in geminal center and T cell zone of spleen, LN, peyer patchTumor necrosis factor superfamilyMutation in TACI, protein encoded by TNFRSF13B, asso c lymphoproliferation include splenomegaly or tonsillar hyperplasia, IgA def with autoimmune thyroiditis
- Molecule implicated genetic studied of CVIDA: ICOS is positive costimulator (expressed CD28)enable T cell interaction with B cell, monocyte and DCB: BAFF-R and TACI are cell surface receptor TNF receptor family play part in B cell differentiation and function.BAFF-BAFF-R interaction provide differentiation of peripheral B cell.Role of BAFF-TACI interaction – TACI signal intracellular through TNF receptor associated factor(TRAF) induce factor k B activationTACI also interact intracellular with calcium modulator and cyclophilin ligand(CAML) interaction with APRIL, TACI regulate isotype switching if Ig and Ab response to T-independent AgC: CD19 is B cell specific cell surface marker, that is part of B cell coreceptor along with CD21 and CD81, CD19 expressed throughout B cell maturation from pro B cell through to plasmablast, coligation of B cell receptor ( BCR) with coreceptor complex of CD19-CD21-CD81 increase B cell signalling.
- ICOS and CD19 deficiency Defect in TACI, BAFF-R and MSH5 remain within CVID
- Prospective cohort 90 CVID in oxford UK F/U 22 yrDisease related phenotype result administration high dose IVIG compare with no disease complicationPt with enteropathy, cytopenia, polyclonal lymphoproliferation treated with high dose IVIG to prevent infection.Lymphoid malignancy also received higher replacement replacement of IgOrgan specific autoimmunity no significant different dose of IVIGPolyclonal lymphoproliferative & LIP receive significant higher dose of IVIG
- Mean trough IgG level to keep pt infection-free.Red bar: CVIDBlue bar: XLA3 different threshold of infection: annual infection score ≤ 4.5, ≤ 2.5, 0Wide range of trough IgG level were infection freeXLA display large range of IgG to maintain infection free stateTrough level to prevent infection higher in XLA compared with CVIDDose range 0.2-1.2 g/kg/mo
- Significant higher mean trough IgG in 2000s compare with 1980s and 1990sSignificant increase dose of IVIG 0.51±0.81 g/kg/mo in 1980s to 0.58 ± 0.28 in 1990s and 0.57± 0.24 in 2000s
- Most pt carry out all normal activity, regual schedule and careful follow upStable pt seen at least yearly interval, aforementioned complication shorter interval such as 3-6 month Routine monitor subject for lung disease no current consensus, HRCT baseline referralRadiosensitive demonstrate in CVIDCVID c chronic cough and/or lung damage prefer LFT;carbon monoxide diffusion, HRCT at 3-4 yr intervalMonitor for autoimmune not require cause CBC & medical oversightRoutine endonot requireIssue of enlarge LN: biposy may be required, lymphoma are extre nodal and appear in unusal location lung or mucosal associated tissue