Background/Aims: Lupus nephritis (LN) is a frequent complication and a major predictor of poor prognosis of systemic lupus erythematosus. Immune complex deposition and T cell infiltration are crucial events in LN pathogenesis. B7-1 (CD80), normally expressed by antigen-presenting cells, is one of the major co-stimulators of T-cell activation through the binding with its counter-receptors CD28 and cytotoxic T-lymphocyte antigen-4. Unexpectedly, B7-1 induction was described at the podocyte level in patients affected by different renal diseases, including LN. These observations suggested a novel exciting function for B7-1 as a biomarker of podocyte injury, and hence that B7-1 inhibitory drugs could serve as podocyte-targeted treatment of intractable renal diseases. However, subsequent studies hardly questioned the reliability of B7-1 detection assays and the therapeutic efficacy of B7-1 blockade in proteinuric patients, casting doubts on B7-1 expression by podocytes. Here, we thoroughly investigated whether B7-1 was indeed expressed by podocytes in LN, before even considering employing B7-1 blockade in patients with severe manifestations of LN and unfavourable prognosis. Methods: Applying different immunohistochemical assays with 4 primary antibodies, we analysed kidney biopsies from 42 LN patients at different stages of the disease, and from NZB/NZW mice, an LN model. Results: B7-1 was not induced in podocytes in human and murine LN; instead its expression was confined to infiltrating inflammatory cells. Conclusion: B7-1 is not expressed by podocytes in LN. A renoprotective effect of B7-1 blockade in LN patients cannot be ruled out but, if confirmed, cannot be the result of an effect on podocyte B7-1.

Keywords:
Lupus nephritis, B7-1, Podocyte
1.
Koutsokeras T, Healy T: Systemic lupus erythematosus and lupus nephritis. Nat Rev Drug Discov 2014;13:173-174.
2.
de Zubiria Salgado A, Herrera-Diaz C: Lupus nephritis: an overview of recent findings. Autoimmune Dis 2012;2012:849684.
3.
Weening JJ, D'Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, Ferrario F, Fogo AB, Ginzler EM, Hebert L, Hill G, Hill P, Jennette JC, Kong NC, Lesavre P, Lockshin M, Looi LM, Makino H, Moura LA, Nagata M: The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004;15:241-250.
4.
Lewis EJ, Schwartz MM: Pathology of lupus nephritis. Lupus 2005;14:31-38.
5.
McAdam AJ, Schweitzer AN, Sharpe AH: The role of B7 co-stimulation in activation and differentiation of CD4+ and CD8+ T cells. Immunol Rev 1998;165:231-247.
6.
Alegre ML, Fallarino F: Mechanisms of CTLA-4-Ig in tolerance induction. Curr Pharm Des 2006;12:149-160.
7.
Goldwich A, Burkard M, Olke M, Daniel C, Amann K, Hugo C, Kurts C, Steinkasserer A, Gessner A: Podocytes are nonhematopoietic professional antigen-presenting cells. J Am Soc Nephrol 2013;24:906-916.
8.
Wu Q, Jinde K, Endoh M, Sakai H: Costimulatory molecules CD80 and CD86 in human crescentic glomerulonephritis. Am J Kidney Dis 2003;41:950-961.
9.
Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, Rastaldi MP, Calvaresi N, Watanabe H, Schwarz K, Faul C, Kretzler M, Davidson A, Sugimoto H, Kalluri R, Sharpe AH, Kreidberg JA, Mundel P: Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest 2004;113:1390-1397.
10.
Garin EH, Diaz LN, Mu W, Wasserfall C, Araya C, Segal M, Johnson RJ: Urinary CD80 excretion increases in idiopathic minimal-change disease. J Am Soc Nephrol 2009;20:260-266.
11.
Garin EH, Reiser J, Cara-Fuentes G, Wei C, Matar D, Wang H, Alachkar N, Johnson RJ: Case series: CTLA4-IgG1 therapy in minimal change disease and focal segmental glomerulosclerosis. Pediatr Nephrol 2015;30:469-477.
12.
Yu CC, Fornoni A, Weins A, Hakroush S, Maiguel D, Sageshima J, Chen L, Ciancio G, Faridi MH, Behr D, Campbell KN, Chang JM, Chen HC, Oh J, Faul C, Arnaout MA, Fiorina P, Gupta V, Greka A, Burke GW 3rd, Mundel P: Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 2013;369:2416-2423.
13.
Fiorina P, Vergani A, Bassi R, Niewczas MA, Altintas MM, Pezzolesi MG, D'Addio F, Chin M, Tezza S, Ben Nasr M, Mattinzoli D, Ikehata M, Corradi D, Schumacher V, Buvall L, Yu CC, Chang JM, La Rosa S, Finzi G, Solini A, Vincenti F, Rastaldi MP, Reiser J, Krolewski AS, Mundel PH, Sayegh MH: Role of podocyte B7-1 in diabetic nephropathy. J Am Soc Nephrol 2014;25:1415-1429.
14.
Laszik Z, Dobi S, Vincenti F: B7-1/CD80 is not a reliable immunophenotypical marker of focal segmental glomerulosclerosis, membranous nephropathy, and diabetic nephropathy. J Am Soc Nephrol 2015, in press.
15.
Gagliardini E, Novelli R, Corna D, Zoja C, Ruggiero B, Benigni A, Remuzzi G: B7-1 is not induced in podocytes of human and experimental diabetic nephropathy. J Am Soc Nephrol 2016;27:999-1005.
16.
Marcela Herrera MS, Molne JC, Perez BS, Valverde AM, Heasman SC, Jermutus L, Baker DJ, Quinn CPM: Assessing the role of B7.1 in diabetic nephropathy. J Am Soc Nephrol 2015;26:128A.
17.
Benigni A, Gagliardini E, Remuzzi G: Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 2014;370:1261-1263.
18.
Larsen CP, Messias NC, Walker PD: B7-1 immunostaining in proteinuric kidney disease. Am J Kidney Dis 2014;64:1001-1003.
19.
Grellier J, Del Bello A, Milongo D, Guilbeau-Frugier C, Rostaing L, Kamar N: Belatacept in recurrent focal segmental glomerulosclerosis after kidney transplantation. Transpl Int 2015;28:1109-1110.
20.
Rutger J, Maas BW, Dijkman H, Haring CM, Deegens J, Wetzels JF: Abatacept treatment and B7-1 immunostaining in patients with primary and post-transplant FSGS. J Am Soc Nephrol 2015;26:454A.
21.
Delville M, Baye E, Durrbach A, Audard V, Kofman T, Braun L, Olagne J, Nguyen C, Deschênes G, Moulin B, Delahousse M, Kesler-Roussey G, Beaudreuil S, Martinez F, Rabant M, Grimbert P, Gallazzini M, Terzi F, Legendre C, Canaud G: B7-1 blockade does not improve post-transplant nephrotic syndrome caused by recurrent FSGS. J Am Soc Nephrol 2015;pii:ASN.2015091002.
22.
Alachkar N, Carter-Monroe N, Reiser J: Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 2014;370:1263-1264.
23.
Kelley VE, Cavallo T: An ultrastructural study of the glomerular slit diaphragm in New Zealand black/white mice. Lab Invest 1976;35:213-220.
24.
Theofilopoulos AN, Dixon FJ: Murine models of systemic lupus erythematosus. Adv Immunol 1985;37:269-390.
25.
Mundel P, Greka A: Developing therapeutic ‘arrows' with the precision of William Tell: the time has come for targeted therapies in kidney disease. Curr Opin Nephrol Hypertens 2015;24:388-392.
26.
Salant DJ: Podocyte expression of B7-1/CD80: is it a reliable biomarker for the treatment of proteinuric kidney diseases with abatacept? J Am Soc Nephrol 2016;27:963-965.
27.
Kinoshita K, Tesch G, Schwarting A, Maron R, Sharpe AH, Kelley VR: Costimulation by B7-1 and B7-2 is required for autoimmune disease in MRL-Faslpr mice. J Immunol 2000;164:6046-6056.
28.
Huang L, Kong Y, Wang J, Sun J, Shi Q, Qiu YH: Reducing progression of experimental lupus nephritis via inhibition of the B7/CD28 signaling pathway. Mol Med Rep 2015;12:4187-4195.
29.
Orencia (abatacept) Prescribing Information. Princeton, Bristol-Myers Squibb, 2013.
30.
Mease P, Genovese MC, Gladstein G, Kivitz AJ, Ritchlin C, Tak PP, Wollenhaupt J, Bahary O, Becker JC, Kelly S, Sigal L, Teng J, Gladman D: Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial. Arthritis Rheum 2011;63:939-948.
31.
Merrill JT, Burgos-Vargas R, Westhovens R, Chalmers A, D'Cruz D, Wallace DJ, Bae SC, Sigal L, Becker JC, Kelly S, Raghupathi K, Li T, Peng Y, Kinaszczuk M, Nash P: The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010;62:3077-3087.
32.
Furie R, Nicholls K, Cheng TT, Houssiau F, Burgos-Vargas R, Chen SL, Hillson JL, Meadows-Shropshire S, Kinaszczuk M, Merrill JT: Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study. Arthritis Rheumatol 2014;66:379-389.
33.
ACCESS Trial Group: Treatment of lupus nephritis with abatacept: the abatacept and cyclophosphamide combination efficacy and safety study. Arthritis Rheumatol 2014;66:3096-3104.
34.
Sandborn WJ, Colombel JF, Sands BE, Rutgeerts P, Targan SR, Panaccione R, Bressler B, Geboes K, Schreiber S, Aranda R, Gujrathi S, Luo A, Peng Y, Salter-Cid L, Hanauer SB: Abatacept for Crohn's disease and ulcerative colitis. Gastroenterology 2012;143:62-69.e4.
35.
Njau MN, Kim JH, Chappell CP, Ravindran R, Thomas L, Pulendran B, Jacob J: CD28-B7 interaction modulates short- and long-lived plasma cell function. J Immunol 2012;189:2758-2767.
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2016
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