SLE science Flashcards
experimental models
Do NZB/NZW mice crossed with nude mice develop SLE, and what does it prove?
Mate mice to produce NZB/W Nu/Nu (no T cell) and compare with nu/+ mice. Only Nu/Nu are protected, no anti ss-DNA but if stimulated can produce ab but no disease. All Nu/+ get gn, die 35 wk, Nu-/Nu- live >45w. T cells mandatory.Mihara M, Ohsugi Y, Saito K, Miyai T, Togashi M, Ono S, et al. Immunologic abnormality in NZB/NZW F1 mice. Thymus-independent occurrence of B cell abnormality and requirement for T cells in the development of autoimmune disease, as evidenced by an analysis of the athymic nude individuals. J Immunol 1988 Jul 1;141(1):85-90.
What experimental proof shows that mice need antibody synthesis to develop lupus?
lpr/lpr mice crossed with Jh knockout (no Ig synthesis), develop no lupus. Littermates with Ig, get severe gn. need b cellsShlomchik MJ, Madaio MP, Ni D, Trounstein M, Huszar D. The role of B cells in lpr/lpr-induced autoimmunity. J Exp Med 1994 Oct 1;180(4):1295-306.
Is BAFF necessary for INF induced SLE aggravation in NZM mice?
Yes. Excess INF production via adenovirus markedly increases SLE disease which can be inhibited by knocking out BAFF or antibody production. NZM adenoINF controls showed same macrophage infiltration, T cell maturation. Macrophage simulation and ratio of memory Th4+/naïve Th4 does not require BAFF (occurs with age) but INF effect does.Jacob N, Guo S, Mathian A, Koss MN, Gindea S, Putterman C, et al. B Cell and BAFF Dependence of IFN-a-Exaggerated Disease in Systemic Lupus Erythematosus-Prone NZM 2328 Mice. J Immunol 2011 Apr 15;186(8):4984-93. USC
Is cellcept a little better or much better than cyclophosphamide in treating lupus nephritis ?
Much better.SLE # early Full Partial resp Remis remismyco 71 56 16 71cyclo 69 42 4 >17Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis.[see comment]. N Engl J Med 2005 Nov 24;353:2219-28.
What were the significant changes during rituximab treatment and Explorer trial-257 patients, 52 weeks?
Explorer trial, Oklahoma, 257 patients,52 wks, intent to treat. Plac 88, ritux 169 1g IVx2,2wks apart. No difference primary and secondary efficacy endpoints. African-American and Hispanic subgroups showed beneficial effect on the primary endpoint. BILAG measures. Rituximab group significant decrease P cells that one year with lower anti-dsDNA, increase C3 and C4. Infections 17% placebo, 9.5 rituximab. Infusion reactions 38 versus 43%. Death 1.1 versus 2.4.Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arth Rheum 2010 Jan;62(1):222-33.
How well does belimumab work in SLE?
867 pts,289 1mg/kg, 290 10 mg/kg, place 288, response index OR=1.5, P1.Navarra SV, Guzman RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011 Feb 26;377(9767):721-31.Bliss 52 study group
What was the antigen on T cells used initially as a target for treating NZB/NZW mice?
A monoclonal antibody developed against L3T4 (CD4) or T4 lymphocytes prevented SLE in lupus prone mice. UCSFWofsy D, Seaman WE. Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4. J Exp Med 1985 Feb 1;161(2):378-91.
Does HIV virus infection protect against SLE?
2 pts developed SLE which went into remission with HIV infection. New OrleansMolina JF, Citera G, Rosler D, Cuellar ML, Molina J, Felipe O, et al. Coexistence of human immunodeficiency virus infection and systemic lupus erythematosus. J Rheumatol 1995;22(2):347-50.
What was the antigen on immune cells used initially as a target for a monoclonal antibody to treat NZB/NZW mice?
A monoclonal antibody developed against L3T4 (CD4) or T4 lymphocytes prevented SLE in lupus prone mice. UCSFWofsy D, Seaman WE. Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4. J Exp Med 1985 Feb 1;161(2):378-91.
How does TNFSF13B (BAFF, B cell Activating Factor) affect follicular helper T cells?
Tfh>TNFSF13B >TNFRSF13C > GC (germinal center).Tfh>INF gamma>dendritic cell> TNFSF13B.TNFRSF17 -> TNFSF13B, TNFRSF13C +>TNFSF13BTfh cells express TNFRSF17 (BCMA) and TNFRSF!3C (BR-3). TNFRSF17 (BCMA) deficiency in T cells promotes GC (germinal center) formation, antibody production, and interferon gamma by Tfh cells through TNFRSF13C. INFg producing Tfh cells increased TNFSF13B expression in dendritic cells. Blocking TNFSF13B or INFg in vivo reduced Tfh cell accumulation and reduced autoimmunity in the TNFRSF17-deficient animals. Tfh like cells that expressed TNFRSF13C but not TNFRSF!7 were elevated in patients with SLE and correlated with serum TNFSF13B and IGFg levels. TNFRSF17 negatively regulates Tfh cell expansion while TNFSF13B signaling through TNFRSF13C promotes Tfc accumulation. The balance between TNFRSF!7 and TNFRSF!3C signaling into Tfh cells serves as a checkpoint of immune tolerance.TNFSF13B (BAFF, B Cell Activating Factor),(BLYS, B Lymphocyte Stimulating factor), (TALL1, TNF- AND APOL-RELATED LEUKOCYTE EXPRESSED LIGAND 1), (THANK,TNF HOMOLOG THAT ACTIVATES APOPTOSIS, NKFB, AND JNK).TNFRSF13C (BCR, B Cell activating Receptor)TNFRSF17 (BCMA, BCM, B Cell Maturation Antigen), ligand for TNFSF13c.Coquery CM, Loo WM, Wade NS, Bederman AG, Tung KS, Lewis JE, et al. BAFF Regulates Follicular Helper T Cells and Affects Their Accumulation and Interferon-g Production in Autoimmunity. Arthritis Rheum 2015 Mar 1;67(3):773-84.
What does TNFSF13B (Baff) do in human SLE?
misnomer survival and diff factor, not activatingTNFSF13B increases B and T cell numbers ->Th1 shift in collagen arthritis -> dec Th17 cells and improvement.TNFRSF17 down regulates Thgc and protects against lupus. Need block receptor combo, not target ligands.Thgc ( T helper germinal center lymphocytes)TNFSF13 (APRIL, A proliferating inducing ligand), (TALL2, TNF- AND APOL-RELATED LEUKOCYTE EXPRESSED LIGAND 2)TNFSF13B (BAFF, B Cell Activating Factor),(BLYS, B Lymphocyte Stimulating factor), (TALL1, TNF- AND APOL-RELATED LEUKOCYTE EXPRESSED LIGAND 1), (THANK,TNF HOMOLOG THAT ACTIVATES APOPTOSIS, NKFB, AND JNK).TNFRSF13C (BCR, B Cell activating Receptor)TNFRSF17 (BCMA, BCM, B Cell Maturation Antigen), ligand for TNFSF13c.Stohl W. Editorial: The BAFFling Immunology of Systemic Lupus Erythematosus: Beyond B Cells. Arthritis Rheum 2015 Mar 1;67(3):612-5.doi: 10.1002/art.38951.USC los angeles
What is the result of Sifalimumab treatment of SLE in the peripheral blood and skin?
Sifalimumab, an anti-interferon antibody reduces IFN signature in peripheral blood cells, and locally in affected skin along with clinical improvement.doi: 10.1186/ar2887.
How effective is Sifalimumab in treating SLE?
In a phase 1 multicenter randomized double-blind dose escalation study sifalimumab showed less need for stronger treatment (12% versus 41%, P = 0.03) and fewer disease flares (3% versus 29%)doi: 10.1136/ard.2010.144485.
What drugs have been tried to treat SLE by interfering with interferon activity?
AMG 811 neutralises IFN-gamma, and sifalimumab neutralises inf-alpha. INF-alpha receptor is targeted by anidrolumab, and IFN-alpha kinoid uses inactivated IFN alpha and keyhole limipet haemocyanin to target the IFN receptors.
