In Vivo Expression Pattern of MICA and MICB and Its Relevance to Auto-Immunity and Cancer

Non-conventional MHC class I MIC molecules interact not with the TCR, but with NKG2D, a C-type lectin activatory receptor present on most NK, γδ and CD8+ αβ T cells. While this interaction is critical in triggering/calibrating the cytotoxic activity of these cells, the actual extent of its in vivo involvement, in man, in infection, cancer or autoimmunity, needs further assessment. The latter has gained momentum along with the reported expansion of peripheral CD4+CD28−NKG2D+ T cells in rheumatoid arthritis (RA). We first initiated to extend this report to a larger cohort of not only RA patients, but also those affected by systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). In RA and SS, this initial observation was further tested in target tissues: the joint and the salivary glands, respectively. In conclusion and despite occasional and indiscriminate expansion of the previously incriminated T cell subpopulation, no correlation could be observed between the CD4+CD28−NKG2D+ and auto-immunity. Moreover, in situ, the presence of NKG2D matched that of CD8+, but not that of CD4+ T cells. In parallel, a total body tissue scan of both MICA and MICB transcription clearly shows that despite original presumptions, and with the exception of the central nervous system, both genes are widely transcribed and therefore possibly translated and membrane-bound. Extending this analysis to a number of human tumors did not reveal a coherent pattern of expression vs. normal tissues. Collectively these data question previous assumptions, correlating a tissue-specific expression/induction of MIC in relevance to auto-immune or tumor processes

Les manifestations articulaires du syndrome de Sjögren primaire

STRASBOURG-Medecine (674822101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Characteristics of patients and healthy controls.

*<p>DAS (Disease Activity Score) 28 for RA, SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) for SLE and mean AVS (AVS: Analogic Visual Scale) of subjective sicca syndrome, asthenia and pain for SS.</p>**<p>Abbreviations: NSAID: Non-Steroidal Anti-Inflammatory Drugs; SMARD: Symptom Modifying Anti-Rheumatic Drugs; DCART: Disease Controlling Anti-Rheumatic Therapy; ANA: antinuclear antibody (indirect immunofluorescence on Hep2 cells), ENA: extractable nuclear antigens; dsDNA: double-stranded DNA, RF: Rheumatoid Factor, CCP: cyclic citrullinated peptide.</p

Expression analysis of <i>MICA</i> and <i>MICB</i> by real-time quantitative PCR in Sjögren's syndrome accessory salivary glands.

<p>Relative expression level of <i>MICA</i> (A) and <i>MICB</i> (B) in Sjögren's syndrome patients as compared to healthy controls. The differences between patients and controls are not significant as assessed by Mann-Whitney <i>U</i> test (α = 0.27 for <i>MICA</i> and α = 0.53 for <i>MICB</i>).</p

MICA expression in Rheumatoid Arthritis synovitis and Sjögren syndrome accessory salivary glands.

<p>Immunohistochemical analysis of (A) (B) RA synovitis and an (C) (D) SS accessory salivary gland stained with an anti-MICA monoclonal antibody. MIC expression is clearly of epithelial/fibroblastic nature in both tissues/organs.</p

Flow cytometric analysis of the CD4⁺NKG2D⁺ population.

<p>This example, taken from one of the two SS patients (Mrs XET) harbouring a particularly high ratio of CD4⁺NKG2D⁺ T cells (36.2%) illustrates the methodology used in order to enumerate these cells in all individuals (controls and patients) included in this work during a routine 50 000 events analysis.</p

CD4⁺NKG2D⁺ T cells autoimmune diseases.

<p>This figure depicts the ratio of CD4⁺NKG2D⁺ T cells within the total peripheral CD4 pool in control, RA, SLE and SS individuals. The variability in SS patients is due to 2 individuals whom represent an unusually high ratio (see main text for explanation). None of the differences is significant as assessed by the Wilcoxon text: p = 0.1658 for controls vs. RA; p = 0.9547 for controls vs. SLE and p = 0.5012 for controls vs. SS.</p