Rheumatic diseases comprise a wide spectrum of different conditions. Some are caused by disturbances of the adaptive immune system, while defects in innate immune responses have been identified for others. In between are a variety of multifactorial diseases for which the evidence for a causative involvement of the adaptive immune system is still controversial. In these cases, availability of novel drugs that target key players of the adaptive immune system have improved our understanding of the relevance of adaptive immunity to the disease process, but it has also generated unprecedented findings.
Rheumatoid arthritis (RA) is a prototypic example of a disease in which the relative contribution of adaptive immunity to disease pathogenesis is incompletely understood. Although numerous markers have been identified that reflect an activated adaptive immune system, several caveats render interpretation of these findings difficult. For one, the very early immune responses initiating disease are likely to take place before an individual is identified as a patient, and are thus difficult to study in the human. Furthermore, increasing evidence points to pathogenetically distinct subgroups within the clinical diagnosis RA, offering the possibility that adaptive immune responses might be relevant to one subgroup but not the other. In addition, many indications for an adaptive immune system involvement are based on associations for which the underlying mechanism is often unknown. Finally, therapeutic interventions targeting the adaptive immune system have generated heterogeneous results.
The present review addresses these issues by placing adaptive immune responses in the context of rheumatic diseases, and by reviewing the evidence for a contribution of adaptive immunity to RA.
Characteristics of the adaptive immune system
Adaptive immunity has evolved as a very powerful, highly specialised and highly optimised tool of host defense. Its classical protagonists are lymphocytes of the T- and B-cell lineage. More recently, natural killer (NK) cells were shown to also have adaptive properties . Effector mechanisms of the adaptive immune system consist of humoral mediators (immunoglobulins and cytokines/chemokines) and cell-mediated effects. A tightly controlled system of developmental checkpoints ensures reactivity against pathogens and foreign antigens but ensures tolerance to self. The most important and exclusive features of adaptive immune responses are specificity for antigen, the ability to modulate and enhance this specificity (affinity maturation), and its ability to generate memory. These features make the adaptive immune system distinct from the phylogenetically older innate immune system, which responds to danger signals and invariantly recognises pathogens based on conserved molecular patterns. Despite this distinction, both systems are functionally highly interconnected.
While it is beyond the scope of this article to review the adaptive immune system in detail, a short overview of its most important features will be presented to understand its possible involvement in autoimmune rheumatic diseases. The developmental pathways of its protagonists are depicted in Figs. 1 and 2 .
