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The Multi-organ Chip - A Microfluidic Platform for Long-term Multi-tissue Coculture

The ever growing amount of new substances released onto the market and the limited predictability of current in vitro test systems has led to a high need ...

Technische Universität Berlin

The role of TLR9 in the development of the autoimmune disease systemic lupus erythematosus is controversial. In different mouse models of the disease, loss of TLR9 abolishes the generation of anti-nucleosome IgG autoantibodies but at the same time exacerbates lupus disease. However, the TLR9-dependent tolerance mechanism is unknown. In this study, we show that loss of TLR9 is associated with low peritoneal B-1b cell numbers and low levels of protective self-reactive IgM serum autoantibodies in lupus-prone FcγRIIB-deficient mice leading to the uncontrolled accumulation of proinflammatory CD4(+) cells and exacerbated autoimmunity. TLR7 signaling was not able to compensate for the loss of TLR9 signaling in peritoneal B-1b cells to induce IgM Abs. Transfer of TLR9-expressing peritoneal B-1b cells from FcγRIIB-deficient mice or of recombinant monoclonal self-reactive IgM Abs was sufficient to reduce the frequency of proinflammatory Th17 cells and lupus disease in FcγRIIB/TLR9 double-deficient mice. Taken together, these data provide evidence for a TLR9-dependent tolerance mechanism of peritoneal B-1b cells generating protective self-reactive IgM in lupus-prone mice to control Th17 cell development and severe autoimmunity.

TLR9 in peritoneal B-1b cells is essential for production of protective self-reactive IgM to control Th17 cells and severe autoimmunity.

Unter Entz&uuml;ndungen induzieren (TD) T-Zell-abh&auml;ngige Protein-Antigene Proinflammatory-T - und B-Zell-Antworten. Toleranz-Induktion von TD-Antigene ohne Costimulation l&ouml;st dagegen die Entwicklung von regulatorischen T-Zellen. Unter beiden Bedingungen IgG-Antik&ouml;rper werden generiert, aber ob sie unterschiedliche immunregulatorische Funktionen haben bleibt.

Toleranz-Induktion mit T-Zell-abh&auml;ngige Protein-Antigene induziert regulatorischen Sialylated IgGs.

In condizioni infiammatorie, antigeni della proteina delle cellule T-dipendenti (TD) inducono risposte di cellule T e B proinfiammatorie. Al contrario, induzione di tolleranza da parte degli antigeni TD senza costimulation innesca lo sviluppo di cellule T regolatorie. Sotto entrambe le condizioni, gli anticorpi IgG sono generati, ma se hanno funzioni diverse immunoregulatory resta sfuggente.

Induzione di tolleranza con antigeni della proteina delle cellule T-dipendenti induce sialilato normativo IgGs.

Under inflammatory conditions, T cell-dependent (TD) protein antigens induce proinflammatory T- and B-cell responses. In contrast, tolerance induction by TD antigens without costimulation triggers the development of regulatory T cells. Under both conditions, IgG antibodies are generated, but whether they have different immunoregulatory functions remains elusive.

Tolerance induction with T cell-dependent protein antigens induces regulatory sialylated IgGs.

Dans des conditions inflammatoires, les antig&egrave;nes prot&eacute;iques d&eacute;pendant des lymphocytes T (TD) induisent des r&eacute;ponses de cellules T et B pro-inflammatoires. En revanche, l&#39;induction de la tol&eacute;rance par des antig&egrave;nes TD sans costimulation d&eacute;clenche le d&eacute;veloppement des lymphocytes T r&eacute;gulateurs. Dans les deux conditions, les anticorps IgG sont g&eacute;n&eacute;r&eacute;s, mais s&#39;ils ont des fonctions diff&eacute;rentes immunor&eacute;gulatrices demeure insaisissable.

Induction de la tol&eacute;rance avec les antig&egrave;nes prot&eacute;iques d&eacute;pendant des lymphocytes T induit sialyl&eacute;s r&eacute;glementaire IgG.

&#x708E;&#x75C7;&#x6761;&#x4EF6;&#x4E0B; T &#x7EC6;&#x80DE;&#x4F9D;&#x8D56; (TD) &#x86CB;&#x767D;&#x6297;&#x539F;&#x8BF1;&#x5BFC;&#x708E;&#x6027; T &#x548C; B &#x7EC6;&#x80DE;&#x53CD;&#x5E94;&#x3002;&#x76F8;&#x6BD4;&#x4E4B;&#x4E0B;&#xFF0C;&#x6CA1;&#x6709;&#x534F;&#x540C;&#x4FE1;&#x53F7; TD &#x6297;&#x539F;&#x8010;&#x53D7;&#x8BF1;&#x5BFC;&#x89E6;&#x53D1;&#x76D1;&#x7BA1; T &#x7EC6;&#x80DE;&#x7684;&#x53D1;&#x80B2;&#x3002;&#x5728;&#x8FD9;&#x4E24;&#x79CD;&#x60C5;&#x51B5;&#x4E0B;&#xFF0C;IgG &#x6297;&#x4F53;&#x751F;&#x6210;&#xFF0C;&#x4F46;&#x4ED6;&#x4EEC;&#x662F;&#x5426;&#x6709;&#x4E0D;&#x540C;&#x7684;&#x514D;&#x75AB;&#x8C03;&#x8282;&#x4F5C;&#x7528;&#x4ECD;&#x7136;&#x662F;&#x53EF;&#x671B;&#x800C;&#x4E0D;&#x53EF;&#x53CA;&#x3002;

&#x4E0E; T &#x7EC6;&#x80DE;&#x4F9D;&#x8D56;&#x86CB;&#x767D;&#x6297;&#x539F;&#x8010;&#x53D7;&#x8BF1;&#x5BFC;&#x8BF1;&#x4F7F;&#x89C4;&#x7BA1; sialylated IgGs&#x3002;

&#x708E;&#x75C7;&#x6027;&#x306E;&#x6761;&#x4EF6;&#x306E;&#x4E0B;&#x3067;&#x86CB;&#x767D;&#x8CEA;&#x306E;&#x6297;&#x539F;&#x3092; T &#x7D30;&#x80DE;&#x306B;&#x4F9D;&#x5B58;&#x3059;&#x308B; (TD) &#x708E;&#x75C7;&#x6027; T &#x304A;&#x3088;&#x3073; B &#x7D30;&#x80DE;&#x306E;&#x53CD;&#x5FDC;&#x3092;&#x8A98;&#x767A;&#x3057;&#x307E;&#x3059;&#x3002;&#x5BFE;&#x7167;&#x7684;&#x306B;&#x3001;&#x5BDB;&#x5BB9;&#x8A98;&#x5C0E;&#x5171;&#x523A;&#x6FC0;&#x304C;&#x306A;&#x304F; TD &#x6297;&#x539F;&#x306B;&#x3088;&#x308B;&#x5236;&#x5FA1;&#x6027; T &#x7D30;&#x80DE;&#x306E;&#x958B;&#x767A;&#x304C;&#x30C8;&#x30EA;&#x30AC;&#x30FC;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;&#x4E21;&#x65B9;&#x306E;&#x6761;&#x4EF6;&#x306E;&#x4E0B;&#x3067; IgG &#x6297;&#x4F53;&#x304C;&#x751F;&#x6210;&#x3055;&#x308C;&#x3001;&#x3057;&#x304B;&#x3057;&#x3001;&#x5F7C;&#x3089;&#x306F;&#x7570;&#x306A;&#x308B;&#x514D;&#x75AB;&#x5236;&#x5FA1;&#x6A5F;&#x80FD;&#x304C;&#x3042;&#x308B;&#x304B;&#x3069;&#x3046;&#x306F;&#x3001;&#x3068;&#x3089;&#x3048;&#x3069;&#x3053;&#x308D;&#x306E;&#x306A;&#x3044;&#x307E;&#x307E;&#x3002;

T &#x7D30;&#x80DE;&#x4F9D;&#x5B58;&#x6027;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x6297;&#x539F;&#x3068;&#x30C8;&#x30EC;&#x30E9;&#x30F3;&#x30B9;&#x8A98;&#x5C0E;&#x898F;&#x5236; sialylated Igg&#x3002;

&#xC5FC;&#xC99D; &#xC131; &#xC870;&#xAC74; &#xD558;&#xC5D0;&#xC11C; T&#xB294; &#xC138;&#xD3EC; &#xC758;&#xC874; (TD) &#xB2E8;&#xBC31;&#xC9C8; &#xD56D; &#xC6D0; proinflammatory T &#xBC0F; B &#xC138;&#xD3EC; &#xC751;&#xB2F5;&#xC744; &#xC720;&#xB3C4;. &#xB300;&#xC870;&#xC801;&#xC73C;&#xB85C;, costimulation &#xC5C6;&#xC774; TD &#xD56D; &#xC6D0;&#xC5D0; &#xC758;&#xD574; &#xAD00;&#xC6A9; &#xC720;&#xB3C4; &#xAC1C;&#xBC1C;&#xC744; &#xADDC;&#xC81C; T &#xC138;&#xD3EC;&#xC758; &#xD2B8;&#xB9AC;&#xAC70;&#xD569;&#xB2C8;&#xB2E4;. &#xB450; &#xC870;&#xAC74; &#xD558;&#xC5D0;&#xC11C; IgG &#xD56D; &#xCCB4;&#xB97C; &#xC0DD;&#xC131; &#xD558;&#xC9C0;&#xB9CC; &#xC560;&#xB9E4; &#xB0A8;&#xC544; &#xB2E4;&#xB978; immunoregulatory &#xAE30;&#xB2A5; &#xD3EC;&#xD568; &#xC5EC;&#xBD80;.

T &#xC138;&#xD3EC; &#xC758;&#xC874; &#xB2E8;&#xBC31;&#xC9C8; &#xD56D; &#xC6D0;&#xC640; &#xAD00;&#xC6A9; &#xC720;&#xB3C4; &#xC720;&#xB3C4; &#xADDC;&#xC815; sialylated IgGs.

Condiciones inflamatorias, ant&iacute;genos de la prote&iacute;na de la c&eacute;lula de T-dependiente (TD) inducen respuestas de c&eacute;lulas T y B proinflamatorias. En cambio, la inducci&oacute;n de la tolerancia por los ant&iacute;genos TD sin coestimulaci&oacute;n desencadena el desarrollo de las c&eacute;lulas T reguladoras. En ambas condiciones, se generan anticuerpos IgG, pero si tienen funciones diferentes inmunoregulador sigue siendo elusiva.

Inducci&oacute;n de la tolerancia con ant&iacute;genos de c&eacute;lulas T-dependiente de la prote&iacute;na induce regulador sialylated IgGs.

Antigen-specific Abs are able to enhance or suppress immune responses depending on the receptors that they bind on immune cells. Recent studies have shown that pro- or antiinflammatory effector functions of IgG Abs are also regulated through their Fc N-linked glycosylation patterns. IgG Abs that are agalactosylated (non-galactosylated) and asialylated are proinflammatory and induced by the combination of T cell-dependent (TD) protein antigens and proinflammatory costimulation. Sialylated IgG Abs, which are immunosuppressive, and Tregs are produced in the presence of TD antigens under tolerance conditions. T cell-independent (TI) B cell activation via B cell receptor (BCR) crosslinking through polysaccharides or via BCR and TLR costimulation also induces IgG Abs, but the Fc glycosylation state of these Abs is unknown. We found in mouse experiments that TI immune responses induced suppressive sialylated IgGs, in contrast to TD proinflammatory Th1 and Th17 immune responses, which induced agalactosylated and asialylated IgGs. Transfer of low amounts of antigen-specific sialylated IgG Abs was sufficient to inhibit B cell activation and pathogenic immune reactions. These findings suggest an immune regulatory function for TI immune responses through the generation of immunosuppressive sialylated IgGs and may provide insight on the role of TI immune responses during infection, vaccination, and autoimmunity.

Article	Year
TLR9 in peritoneal B-1b cells is essential for production of protective self-reactive IgM to control Th17 cells and severe autoimmunity. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 21859955	2011
Tolerance induction with T cell-dependent protein antigens induces regulatory sialylated IgGs. The Journal of allergy and clinical immunology\| PubMed ID: 22502800	2012
T cell-independent B cell activation induces immunosuppressive sialylated IgG antibodies. The Journal of clinical investigation\| PubMed ID: 23979161	2013

Alexandra K. Lorenz

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