T cells and autoimmune kidney disease

Abstract

Glomerulonephritis is traditionally considered to result from the invasion of the kidney by autoantibodies and immune complexes from the circulation or following their formation in situ, and by cells of the innate and the adaptive immune system. The inflammatory response leads to the proliferation and dysfunction of cells of the glomerulus, and invasion of the interstitial space with immune cells, resulting in tubular cell malfunction and fibrosis. T cells are critical drivers of autoimmunity and related organ damage, by supporting B-cell differentiation and antibody production or by directly promoting inflammation and cytotoxicity against kidney resident cells. T cells might become activated by autoantigens in the periphery and become polarized to secrete inflammatory cytokines before entering the kidney where they have the opportunity to expand owing to the presence of costimulatory molecules and activating cytokines. Alternatively, naive T cells could enter the kidney where they become activated after encountering autoantigen and expand locally. As not all individuals with a peripheral autoimmune response to kidney antigens develop glomerulonephritis, the contribution of local kidney factors expressed or produced by kidney cells is probably of crucial importance. Improved understanding of the biochemistry and molecular biology of T cells in patients with glomerulonephritis offers unique opportunities for the recognition of treatment targets for autoimmune kidney disease.

iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

“…LN affects 40%-60% of adult SLE patients (1) and is characterized by Ab and complement deposition in the kidneys (2,3). IC deposition initiates recruitment and activation of neutrophils and monocytes that produce inflammatory mediators to amplify injury, often resulting in irreversible loss of renal function, i.e., endstage fibrosis (4)(5)(6).…”

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“…These nonproliferating cells are involved in the pathogenesis of many autoimmune diseases, including iMGN, 5 and could be responsible for anti-CD20 MAb-resistant or relapsing nephrotic syndrome and the inability to reach sustained complete remission in nearly 50% of patients with recurrent iMGN after kidney transplant 2 and 80% of patients with iMGN in the native kidney, 8 irrespective of the immunosuppressive regimen. Moreover, the better complete remission rates (52%) 2 in patients with recurrent iMGN posttransplant versus 13.6% (as reported in the largest observational study where rituximab was used as rescue or first-line therapy 9 ) to 19% (first randomized controlled trial where rituximab was added to a conservative antiproteinuric nonimmunosuppressive therapy 8 ) in the native kidney setting highlight the important role of T-cell-targeted therapies, which seem to play an important role in autoimmune kidney diseases 3 and may add value to anti-CD20 MAb treatment by increasing the rate of remission in patients with recurrent disease posttransplant versus those with native iMGN. Surprisingly, the new-generation anti-CD20 MAb ofatumumab failed to demonstrate superiority over rituximab as a salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma, as shown in a recent randomized controlled trial involving 447 patients.…”

“…1 These inconsistencies coupled with the superior complete and sustained remission rates in recurrent disease after kidney transplant versus rates of complete and partial remission, relapse, and resistance in the native kidney with iMGN2 implies the existence of different immu nopathogenic signatures that may be operational, either isolated or combined, in the pathogenesis of iMGN. These pathogenic mechanisms involve primarily B-cell-mediated pathways with a T-cell help component 3,4 and distinct autoantibody-and alloantibody-secreting mechanisms involving different B-cell lineages present in separate compartments. These compartments include a CD20+-activated B cell compartment found in spleen and lymph nodes, which generate the circulating CD19+/CD20-plas mablasts, and short-lived plasma cells (SLMPC) in the blood, as well as a second compartment that consists of CD19-/CD20-/CD38+/CD138+ long-lived memory plasma cells (LLMPC) niched naturally in the bone marrow and ectopically in the native or grafted inflamed kidney ( Figure 1 and Table 1).…”

“…Given the existence of different potential immunopathogenic signatures that may be operational in the pathogenesis of iMGN, there is an important need for the development of immunologic or other biomarkers to help identify patients who are likely to successfully respond to T-cell-targeted therapy, 3 B-lymphocyte depletion, 5 or ultimately a combination of both. 12 Furthermore, in addition to the measurement of already known nephritogenic autoantibodies or alloantibodies in iMGN, such as anti-PLA2R and anti-THSD7A antibodies and those yet to be identified, which may have diagnostic and prognostic importance 8,9 ; immunologic monitoring should be introduced in order to assess not only CD19 and CD20 markers [6][7][8][9][10] but also CD138 and CD34 markers of short-and long-lived memory plasma cells, mainly in patients with relapsed and resistant disease.…”

“…12 Furthermore, in addition to the measurement of already known nephritogenic autoantibodies or alloantibodies in iMGN, such as anti-PLA2R and anti-THSD7A antibodies and those yet to be identified, which may have diagnostic and prognostic importance 8,9 ; immunologic monitoring should be introduced in order to assess not only CD19 and CD20 markers [6][7][8][9][10] but also CD138 and CD34 markers of short-and long-lived memory plasma cells, mainly in patients with relapsed and resistant disease. [3][4][5][6][7]12 Potential therapeutic targets against plasma cells in the bone marrow niche are emerging (Figure 3). 5 Depleting plasma cells could eliminate pathogenic alloantibody-or autoantibody-producing B cells and interrupt cellular functions of B cells that enhance pathogenic T-cell activation.…”