A role for the B-cell CD74/macrophage migration inhibitory factor pathway in the immunomodulation of systemic lupus erythematosus by a therapeutic tolerogenic peptide

Abstract

SummarySystemic lupus erythematosus (SLE) is an autoimmune disease that involves dysregulation of B and T cells. A tolerogenic peptide, designated hCDR1, ameliorates disease manifestations in SLE-afflicted mice. In the present study, the effect of treatment with hCDR1 on the CD74/macrophage migration inhibitory factor (MIF) pathway was studied. We report here that B lymphocytes from SLE-afflicted mice express relatively elevated levels of CD74, compared with B cells from healthy mice. CD74 is a receptor found in complex with CD44, and it binds the pro-inflammatory cytokine MIF. The latter components were also up-regulated in B cells from the diseased mice, and treatment with hCDR1 resulted in their down-regulation and in reduced B-cell survival. Furthermore, up-regulation of CD74 and CD44 expression was detected in brain hippocampi and kidneys, two target organs in SLE. Treatment with hCDR1 diminished the expression of those molecules to the levels determined for young healthy mice. These results suggest that the CD74/MIF pathway plays an important role in lupus pathology.

B cells promote tumor progression in a mouse model of HPV‐mediated cervical cancer

“…They expressed lower levels of MHC II and CD86 molecules as compared to naive B cells, higher levels of PD‐L1, CD39 and Ly6A/E and downregulated genes coding for CD74 and CD79a. CD74 is a chaperone molecule of MHC II that promotes its translocation from the endoplasmic reticulum to endocytic compartments during antigen presentation . The downregulation of CD79a in TC‐1 dLN B cells, which is part of the BCR and contains ITAM motifs, could be due to B cell differentiation to plasma cells and correlates with the increase of Igs in TC‐1‐bearing mice.…”

“…CD74 is a chaperone molecule of MHC II that promotes its translocation from the endoplasmic reticulum to endocytic compartments during antigen presentation. 27 The downregulation of CD79a in TC-1 dLN B cells, which is part of the BCR and contains ITAM motifs, could be due to B cell differentiation to plasma cells 38 and correlates with the increase of Igs in TC-1-bearing mice. B cells have been shown to exert immunoregulatory functions by producing adenosine through the CD39 and CD73 ectonucleotidases.…”

The Tolerogenic Peptide, hCDR1, Down-Regulates the Expression of Interferon-α in Murine and Human Systemic Lupus Erythematosus

“…Those beneficial effects resulted from the effects of hCDR1 on different immune cell types (including dendritic [22], T [9], [17], [34] and B cells [20], [21], [35]) and on cytokines [9], [11]. Thus, hCDR1 down regulated (in vivo and in vitro, in murine SLE models and in human lupus) pro-inflammatory cytokines [11], [23], [24], apoptotic factors [18], [19], [23], [24], [36], B-cell stimulatory factors (BAFF/BLyS) [20], [24] and up regulated immunosuppressive cytokines [9], [11], [23], [24], [37] with the induction of CD4+CD25+FoxP3+regulatory T-cells [15], [23].…”

“…Treatment with hCDR1 affected the B cell compartment as well. Thus, it down regulated the rate of maturation, differentiation and survival of B cells by reducing the levels of B cell activating factor (BAFF, BLyS) [20] as well as of molecules of the CD74/MIF pathway on B cells [21]. In addition, hCDR1 was shown to induce dendritic cells with immature phenotype and suppressed function that down regulate autoreactive T cells [22].…”

CD74 Deficiency Mitigates Systemic Lupus Erythematosus–like Autoimmunity and Pathological Findings in Mice

“…Increased expression of CD74 also occurred in B cells, kidneys, and brains from mice with induced or spontaneous systemic lupus erythematosus (SLE)-like autoimmunity and pathology (10). SLE, a prototypic systemic autoimmune disease, exhibits B-cell hyperreactivity and production of autoantibodies against nuclear proteins and nucleic acids (11, 12).…”