V. Yilmaz 1, P. Oflazer 2, F. Aysal 3, Y.G. Parman 2, H. Direskeneli 4, F. Deymeer 2, G. Saruhan-Direskeneli 1 I.U. Istanbul Medical Faculty Departments.

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Presentation transcript:

V. Yilmaz 1, P. Oflazer 2, F. Aysal 3, Y.G. Parman 2, H. Direskeneli 4, F. Deymeer 2, G. Saruhan-Direskeneli 1 I.U. Istanbul Medical Faculty Departments of Physiology and Neurology, (3) Bakirkoy Hospital (4) Marmara University, Faculty of Medicine, Division of Rheumatology, Istanbul/Turkey

Neuromuscular junction Vincent A,

Auto-antibodies in MG Anti-AChR antibody (AP) % IgG1-2a (Complement activated) Seronegative MG 15-10% Anti-AChR (-) Anti-MuSK (-) (SN) 56% 5-8% Anti-MuSK (Muscle specific kinase) (MP) 44% 4-6% IgG4 and IgG1 (Complement activity?)

b |Complement C9 deposition in MG NT: nerve terminal PSF: postsynaptic folds Role of the complement activation in anti- AChR (+) MG

Role of Cytokines in Regulation of Antibody Production T cell help CD40L (Ligand) interaction Cytokine

Basal Cytokine Secretion of PBMC in MG IFN  IL-13 IL-10 N MG CON * p< N MG CON N MG CON PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC)

CD3 Stimulation of MG PBMC IFN  IL-13 IL-10 N SN MP AP * p=0.001 * p<0.001 N SN MP AP N SN MP AP

Study Group N ♂♀ Mean age Immunosuppres sive treatment MG AP MP SN Rheumatoid Arthritis (RA) Controls

B Cells in the Periphery SUBGROUPS of MG % of CD19+CD27+

BAFF RECEPTOR (BAFFR) in MG p: 0.001p: SUBGROUPS of MG

T Helper Cells (Th2): CD4+CCR4+ p: 0.04 p: 0.015

T cell help CD40L (Ligand) interaction Cytokine Role of Cytokines in Regulation of Antibody Production

T Cell Help: CD40L expression in isolated CD4+ T cells BOTH MG and CON were higher than RA CON

NO TREATMENT MP> RA SN>RA T Cell Help: CD40L expression in CD4+ T cells

T Cell Help: IL-10 and IFN-  expression in isolated CD4+ T cells CON

IL-10 and IL-6 expression in isolated CD19+ B cells CON

B cell activation B cell receptor (BCR = Ig)Specific antigenAChR/MuSK ImmunoglobulinPoly Ig T cell helpCD40- CD40L B cell co-receptors TLRTLR-9CpG/non-CpG

TLR Stimulation of B Cells

Regulatory Role of B Cells by IL-10 Secretion

IL-10 Response to Nonspecific Stimuli Basal Poly Ig CpG Basal: SN<CON* MP<CON* RA<CON* AP<CON Poly Ig: SN<CON* RA<CON* MP<CON AP<CON

Basal tAChR rMuSK IL-10 production of B cells in response to specific antigens AChR: MP<CON* RA<CON* SN<CON AP<CON No subgroup related antigen specific responses

IL-6 Response to Non-specific Stimuli Basal Poly Ig CpG Basal: MP<CON* RA<CON* AP<CON SN<CON Poly Ig: MP<CON* AP<CON* RA<CON* SN<CON

AChR MP < CON* RA < CON* IL-6 Response to Specific Stimuli No subgroup related antigen specific responses

TNF-  Response to Stimulation Basal Poly Ig CpG Poly Ig: MP<CON* SN<CON* No differences in responses to AChR and MuSK between groups

TNF-  Response to Non-specific Stimuli Basal Poly Ig CpG Basal: MP<CON* AP<CON* RA<CON* Poly Ig: MP<CON* SN>CON

TNF-  Response to Specific Stimuli AChR: RA<CON* Basal tAChR rMuSK No subgroup related antigen specific responses

IL-12p40 Secretion in Response to Non-specific Stimulation No differences in responses to AChR and MuSK between groups AP MP SN RA CON

CONCLUSION B cell related or B cell derived cytokine activity in antibody- based subgroups of MG did not reveal a specific pattern for disease development The differences between RA and MG point to differential cytokine effects in these diseases Untreated patients in all subgroups are needed to clairify the differential features in this disease.

PLASMA vs. CULTURE SUPERNATANTS Only RA higher than MG and controls IL-10 Lower in AP compared to RA and Controls IL-13 Higher in RA only

mRNA expression in CD19+ B cells

IL-6 Response to Specific Stimuli in Non-treated Patients

IL-6 Response to Non-specific Stimuli in Non- treated Patients Basal Poly Ig CpG

IL-6 production of B cells in response to specific antigens

TNF-  Response to Non-specific Stimuli in Un- treated Patients

TNFB-

TNFA Antigen-Specific Stimulation

IL-10 Response to Nonspecific Stimuli in unteated MG SN<CON <RA