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Adaptive immunity in rheumatic diseases – Bystander or pathogenic player?

https://doi.org/10.1016/j.berh.2011.11.005Get rights and content

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.

Section snippets

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 [1]. 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

Antigen specificity

Both the adaptive and the innate immune systems share the ability to differentiate self from non-self, and to sense and to react to situations that potentially endanger the host (mediated by so-called ‘danger signals’) [2]. Besides recognising evolutionary conserved structures on pathogens, the innate immune system screens cells stereotypically for the presence of cell-surface major histocompatibility (MHC) class I molecules, and will attack cells that lack this molecule (such as certain

Affinity maturation

While T cells undergo lineage commitment dependent on the cytokine environment in which they are activated (Fig. 1) [11], [12], most B cells undergo somatic mutation and class switch recombination before developing into antibody-producing plasma or memory cells (Fig. 2). During this development, B cells in germinal centres introduce point mutations in the variable region genes of their surface-expressed B-cell receptors, thereby modulating the affinity by which the receptors recognise antigen.

Memory

The adaptive immune system has the ability to establish antigen-specific immune responses that persist even though the antigen that originally induced the response has long been cleared [25]. Following antigen encounter and clearance, a fraction of activated T cells survives the retraction phase of the initial immune response and either circulates through secondary lymphoid organs or homes to mucosal tissues. This heterogeneous group of memory T cells can quickly react to a second encounter of

Tolerance

Mechanisms of central tolerance operational in thymus and bone marrow have, in part, been discussed above. Defects in molecules involved in the process of central tolerance can lead to the development of autoimmune disease, as illustrated and exemplified by autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (APECED; also known as autoimmune polyglandular syndrome type I), an autoimmune syndrome caused by an inactivating mutation in the gene encoding Aire (autoimmune regulator)

Adaptive immunity in the context of rheumatic diseases

Pathogenic involvement of adaptive immunity in a disease process is suspected in the case of detectable markers of antigen-specific B- or T cell activation. In many infectious diseases, pathogen-specific B- or T-cell responses can readily be detected and, in some cases, allow differentiation between recent infection, latency or clearance of the pathogen. Infection with hepatitis B virus, for example, can be characterised on the basis of an antibody response against antigens derived from the

Adaptive immune system involvement of pathogenetic relevance

Disturbances of the adaptive immune system are generally viewed as a loss of tolerance to self, resulting in autoimmunity. The most broadly accepted definition of autoimmunity is based on criteria first put forward by Witebsky in 1957 and revised by Rose in 1993 [49], [50]. Following these criteria, an autoimmune disease must display an antibody or a cell-mediated immune response targeting a defined self-antigen. In addition, it is postulated that transfer of the self-reactive antibody or cell

Adaptive immunity in RA

In RA, it is still unclear whether the pathogenetic mechanisms thought to be involved in disease induction are also operational in established disease. In addition, it is likely that early immunological events take place in secondary lymphoid organs, whereas disease perpetuation could be driven by events in the inflamed synovium. The very first immune reactions leading to RA are extremely difficult, if not impossible, to study in human disease. ACPA and RF have both been detected in sera

Heterogeneity of the effects of targeting the adaptive immune response in RA

Several strategies have been developed that directly target the adaptive immune response in RA. Some of these have led to the approval of therapeutic agents, while others have failed in clinical trials. Effective approaches comprise both B- and T-cell-targeted therapies, but ineffective compounds are also found in both groups. These differential effects could in part be explained by differential pathogenetic mechanisms underlying disease subsets. In addition, timing of the intervention could be

Summary

The adaptive immune system is able to generate an almost unlimited diversity of receptors for antigen. In addition, it can memorise antigen recognition for the lifetime of its host. This diversity comes with the generation of autoreactive B- and T-cell clones, which requires central and peripheral as well as tissue-based checkpoints and regulatory mechanisms to avoid the development of autoimmunity. Failure of these mechanisms at numerous stages has been described, some of which result in

Conflict of interest statement

The authors declare no conflict of interests.

Acknowledgements

This work was supported by the European Union 6th Framework Programme Integrated Project Autocure.

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