Role of major histocompatibility complex class II expression by non-hematopoietic cells in autoimmune and inflammatory disorders: facts and fiction.

It is well established that interactions between CD4(+) T cells and major histocompatibility complex class II (MHCII) positive antigen-presenting cells (APCs) of hematopoietic origin play key roles in both the maintenance of tolerance and the initiation and development of autoimmune and inflammatory disorders. In sharp contrast, despite nearly three decades of intensive research, the functional relevance of MHCII expression by non-hematopoietic tissue-resident cells has remained obscure. The widespread assumption that MHCII expression by non-hematopoietic APCs has an impact on autoimmune and inflammatory diseases has in most instances neither been confirmed nor excluded by indisputable in vivo data. Here we review and put into perspective conflicting in vitro and in vivo results on the putative impact of MHCII expression by non-hematopoietic APCs--in both target organs and secondary lymphoid tissues--on the initiation and development of representative autoimmune and inflammatory disorders. Emphasis will be placed on the lacunar status of our knowledge in this field. We also discuss new mouse models--developed on the basis of our understanding of the molecular mechanisms that regulate MHCII expression--that constitute valuable tools for filling the severe gaps in our knowledge on the functions of non-hematopoietic APCs in inflammatory conditions.

Whole body low dose irradiation improves the course of beginning polyarthritis in human TNF-transgenic mice.

Rheumatoid arthritis (RA) displays a chronic inflammatory joint disease, accompanied by symmetric polyarthritis (PA) which evokes synovial inflammation, cartilage damage, and bone erosion. Patients with RA are routinely treated by immunosuppressive drugs. The therapy of inflammatory diseases and degenerative disorders with Low-dose radiotherapy (LD-RT) (single doses from 0.3 to 1.0 Gy) represents a low cost therapy with low toxicity, and is able to substitute at least in part treatment with drugs. The efficiency of LD-RT has already been proven in several animal models of inducible arthritis. In the present study we used a human TNF transgenic mouse model to examine the effects of LD-RT on PA. We observed a significant temporal improvement of the clinical progression of disease when mice were irradiated at the beginning of the disease. These data emphasize the role of LD-RT in clinical settings to treat patients with chronic and degenerative disorders and diseases.

Clearance deficiency--a potential link between infections and autoimmunity.

Cell death plays a pivotal role in development and homeostasis of multicellular organisms. Apoptosis represents the physiological and anti-inflammatory form of cell death. Advanced apoptosis and necrosis are rather pro-inflammatory. Several "find-me"- and "eat-me"-signals support the "swift and silent" removal of dying cells. If the highly controlled process of dying cell removal fails, they may progress to secondary necrosis and provoke autoimmunity. There are several reports describing clearance deficiency as a possible mechanism in the etiopathogenesis of SLE. Under certain conditions, increased phagocytosis of nuclear material may be found in a subgroup of patients with SLE. Complement proteins and autoantibodies may modify engulfment of apoptotic remnants and shift the clearance process towards inflammation. Taken together, clearance deficiency leads to the accumulation of apoptotic remnants and breaking of tolerance to self. Besides, enhanced uptake of nuclear immune complexes may maintain chronic autoimmunity in patients with SLE.