Differential expression and regulation of the non-integrin 37/67-kDa laminin receptor on peripheral blood leukocytes of healthy individuals and patients with rheumatoid arthritis.

The non-integrin 37/67-kDa laminin receptor (LAMR1) is a complex protein with diverse functions. LAMR1 is widely expressed in epithelial cells and recently it was reported on neutrophils and a subset of activated T cells. Ligation of LAMR1 on peripheral blood mononuclear cells (PBMC) downregulated LPS-induced TNFα production, suggesting immune functions. However, its expression on primary monocytes remain unknown. Interestingly, LAMR1 mRNA is downregulated in PBMC of patients with early rheumatoid arthritis (RA), and low gene expression is an independent predictor of poor response to anti-TNFα treatment, suggesting a role in RA pathogenesis. We found LAMR1 was constitutively expressed on all peripheral blood monocytes and a subset of B cells from healthy individuals and patients with RA and it was abundantly present in synovial tissue of patients with RA. On monocytes and synovial tissue lower levels of LAMR1 expression tended to correlate with increased disease activity scores. In vitro treatment of monocytes with IFNγ or IL-10 up-regulated surface LAMR1 in healthy individuals and patients with RA with greater effects observed in healthy individuals. Importantly, treatment with IFNγ significantly increased specific binding of monocytes to laminin-1. TNFα and IL-1ß caused marginal downregulation of LAMR1 in patients but effects in controls were variable. Taken together, constitutively expressed LAMR1 on monocytes is differentially regulated by pro-inflammatory and immune-regulatory cytokines suggesting LAMR1 may regulate the threshold and amplitude of their activation and migration. Decreased levels in patients with RA may indicate loss of this potentially critical homeostatic regulation thereby contributing to the excessive inflammation.

Termination of immune activation: an essential component of healthy host immune responses.

The ideal immune response is rapid, proportionate and effective. Crucially, it must also be finite. An inflammatory response which is disproportionate or lasts too long risks injury to the host; chronic un-regulated inflammation in autoimmune diseases is one example of this. Thus, mechanisms to regulate and ultimately terminate immune responses are central to a healthy immune system. Despite extensive knowledge of what drives immune responses, our understanding of mechanisms of immune termination remains relatively sparse. It is clear that such processes are more complex than a one-dimensional homeostatic balance. Recent discoveries have revealed ever more nuanced mechanisms of signal termination, such as intrinsically self-limiting signals, multiple inhibitory mechanisms acting in tandem and activating proteins behaving differently in a variety of contexts. This review will summarise some important mechanisms, including termination by immunoreceptor tyrosine-based inhibitory motifs (ITIM), inhibition by soluble antagonists, receptor endocytosis or ubiquitination, and auto-inhibition by newly synthesised intracellular inhibitory molecules. Several recent discoveries showing immunoreceptor tyrosine-based activation motifs transducing inhibitory signals, ITIM mediating activating responses and the possible roles of immunoreceptor tyrosine-based switch motifs will also be explored.