Cellular and Molecular Mechanisms of Autoimmunity and Lupus Nephritis.

Autoimmunity involves immune responses directed against self, which are a result of defective self/foreign distinction of the immune system, leading to proliferation of self-reactive lymphocytes, and is characterized by systemic, as well as tissue-specific, inflammation. Numerous mechanisms operate to ensure the immune tolerance to self-antigens. However, monogenetic defects or genetic variants that weaken immune tolerance render susceptibility to the loss of immune tolerance, which is further triggered by environmental factors. In this review, we discuss the phenomenon of immune tolerance, genetic and environmental factors that influence the immune tolerance, factors that induce autoimmunity such as epigenetic and transcription factors, neutrophil extracellular trap formation, extracellular vesicles, ion channels, and lipid mediators, as well as costimulatory or coinhibitory molecules that contribute to an autoimmune response. Further, we discuss the cellular and molecular mechanisms of autoimmune tissue injury and inflammation during systemic lupus erythematosus and lupus nephritis.

Comparative immunomodulation potential of Tinospora cordifolia (Willd.) Miers ex Hook. F., Tinospora sinensis (Lour.) Merrill and Tinospora cordifolia growing on Azadirachta indica A. Juss.

Guduchi has been widely used in the traditional medicine as an immunomodulator. Description of guduchi in Ayurvedic literature resemble with T. sinensis rather than with commonly available T. cordifolia and hence this may be used as substitutes for T. sinensis. T. cordifolia growing on Azadirachta indica commonly called Neem-guduchi has more immunomodulatory potential. Thus, immunomodulatory activity of three Tinospora spp. was assessed by checking humoral and cell mediated immune responses to the antigenic challenges with sheep RBCs and by neutrophil adhesion tests on albino Wistar rats using Guduchi-Satwa, a well known dosage form. Results revealed that Neem-guduchi possesses higher immunomodulatory potential at the dose of 300 mg/kg, po and validated the traditional claim. Hence, Neem-Guduchi can be employed in immunomodulatory formulation prepared using guduchi.

Podocytes produce homeostatic chemokine stromal cell-derived factor-1/CXCL12, which contributes to glomerulosclerosis, podocyte loss and albuminuria in a mouse model of type 2 diabetes.

AIMS/HYPOTHESIS: Chemokine (C-X-C motif) ligand 12 (CXCL12) (also known as stromal cell-derived factor-1 [SDF-1]-alpha) is a homeostatic chemokine with multiple roles in cell homing, tumour metastasis, angiogenesis and tissue regeneration after acute injuries. However, its role in chronic diseases remains poorly defined, e.g. in chronic glomerular diseases like diabetic glomerulosclerosis. We hypothesised that CXCL12 may have a functional role during the evolution of diabetic glomerulosclerosis, either by assisting glomerular repair or by supporting the maladaptive tissue remodelling in response to hyperglycaemia and glomerular hyperfiltration. METHODS: To define the functional role of CXCL12 in the progression of glomerular disease, we used the CXCL12-specific inhibitor NOX-A12, an L: -enantiomeric RNA oligonucleotide (Spiegelmer). A mouse model of type 2 diabetes (db/db mice) was used. Male db/db mice, uni-nephrectomised at 6 weeks of age, received subcutaneous injections with a PEGylated form of NOX-A12, non-functional control Spiegelmer or vehicle on alternate days from 4 to 6 months of age. RESULTS: Immunostaining localised renal CXCL12 production to glomerular podocytes in db/db mice with early or advanced diabetic nephropathy. CXCL12 inhibition significantly reduced the degree of glomerulosclerosis, increased the number of podocytes, prevented the onset of albuminuria and maintained the peritubular vasculature without affecting blood glucose levels, body weight or glomerular macrophage infiltration. CONCLUSIONS/INTERPRETATION: We conclude that podocytes produce CXCL12, which contributes to proteinuria and glomerulosclerosis in our mouse model of type 2 diabetes. This novel pathomechanism provides the first evidence that CXCL12 could be a therapeutic target in (diabetic) glomerulosclerosis.