ARTHRITIS & RHEUMATISM Vol. 56, No. 7, July 2007, pp 2362–2370 DOI 10.1002/art.22654 © 2007, American College of Rheumatology Predominance of CD8+ T Lymphocytes Among Periglomerular Infiltrating Cells and Link to the Prognosis of Class III and Class IV Lupus Nephritis Lionel Couzi, 1 Pierre Merville, 1 Colette Deminie `re, 2 Jean-Franc ¸ois Moreau, 1 Christian Combe, 2 Jean-Luc Pellegrin, 3 Jean-Franc ¸ois Viallard, 3 and Patrick Blanco 1 Objective. Recent studies have revealed a poten- tial implication of CD8 T lymphocytes in the patho- genesis of systemic lupus erythematosus (SLE) through their ability to induce tissue damage. The aim of the present study was to analyze the localization of CD8 cells in the kidneys of patients with class III and class IV lupus nephritis and to establish correlations with his- tologic, biologic, and clinical features of SLE. Methods. Twenty-five consecutive SLE patients with class III or class IV lupus nephritis were enrolled. Phenotype analyses of blood lymphocytes and renal immunohistochemistry studies were performed. Results. CD8 T cells were the predominant kidney-infiltrating subset of cells. The mean  SD numbers of CD8 T cells and CD4 T cells were 66.2  65.2/mm 2 and 19.3  29.4/mm 2 , respectively. There was a significant correlation between the percentage of blood CD3,CD8,DR cells and the total number of renal CD8 T cells (r  0.42, P  0.039). Renal CD8 T cell infiltration correlated well with the renal activity index (r  0.63, P  0.0007) and with high serum creatinine levels (r  0.75, P  0.0001). This CD8 T cell infiltrate, which was predominantly in the peri- glomerular area, was correlated with cellular crescents and Bowman’s capsule rupture and was associated with a poor response after conventional induction therapy. Conclusion. CD8 T lymphocytes infiltrate the periglomerular area in patients with severe (class III and class IV) lupus nephritis and are linked to a poor outcome after induction therapy. These results reveal a new potential effector pathway operant in lupus nephritis. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiorgan involvement char- acterized by an immune response against nuclear com- ponents (1). Environmental triggers such as viruses (2) are likely to act in the context of susceptibility genes, including genes involved in antigen/immune complex clearance, lymphoid signaling, or apoptosis, among sev- eral others, accounting for the reason the pathogenesis of this disease remains largely unexplained (3). SLE patients experience a waxing and waning disease course and a wide array of clinical manifestations, reflecting the systemic nature of the disease. The kidneys may become the target of SLE-induced inflammation at disease onset or during the disease course in up to 60% of cases (4). There are numerous studies demonstrating that immune complex deposition directly induces inflamma- tion and tissue damage. However, animal models and recent studies in humans support the idea that other effector pathways, including cytotoxic T lymphocytes, could be involved in the pathogenesis of SLE. For example, STAT-4–deficient NZM2328 mice develop accelerated nephritis and increased mortality rates, with lower titers of anti-DNA antibodies (5). In another mouse model, breaking tolerance to double-stranded DNA (dsDNA), nucleosome, and other nuclear antigens was not required for the pathogenesis of lupus glomer- ulonephritis, implying the involvement of autoreactive effector T cells in tissue lesions (6). More specifically, cytotoxic T lymphocytes have been proposed to be 1 Lionel Couzi, MD, Pierre Merville, MD, PhD, Jean-Franc ¸ois Moreau, MD, PhD, Patrick Blanco, MD, PhD: CHU, and UMR- CNRS 5164, Universite ´ Victor Segalen Bordeaux 2, Bordeaux, France; 2 Colette Deminie `re, MD, Christian Combe, MD, PhD: CHU, Bor- deaux, France; 3 Jean-Luc Pellegrin, MD, PhD, Jean-Franc ¸ois Viallard, MD, PhD: CHU, Bordeaux, France. Address correspondence and reprint requests to Patrick Blanco, MD, PhD, UMR-CNRS 5164, Universite ´ Victor Segalen Bordeaux 2, 146 Rue Le ´o Saignat, 33076 Bordeaux, France. E-mail: patrick.blanco@u-bordeaux2.fr. Submitted for publication September 29, 2006; accepted in revised form March 16, 2007. 2362