Juvenile idiopathic arthritis (JIA): How do genes contribute to onset of this autoimmune disease? What about the environment?
Both the genetic groundwork of juvenile idiopathic arthritis (JIA) and the influence of the environment on onset of the disease have thus far seen little research. One of the reasons for this is surely that JIA is a rare disease: only one in a thousand children suffer from juvenile idiopathic arthritis. With such a small number of patients, it is naturally difficult to carry out meaningful studies.
Insights and hypotheses about the epidemiology and pathomechanism of other autoimmune diseases have only in recent years begun to be carried over to JIA and confirmed for this autoimmune disorder.I have collected several current studies, and have compiled the essential aspects of the latest information on the subject for you. A selection of relevant literature is presented at the end of this blog post.
For a quick introduction to the topic, I particularly recommend the review by Sampath Prahalad and David N. Glass, which you can download for free as an open access article (open access, full text article: A Comprehensive Review of the Genetics of Juvenile Idiopathic Arthritis in Pediatric Rheumatology), as well as the Rheumatology article by Justine A. Ellis, Jane E. Munro, and Anne-Louise Ponsonby (link to the abstract: Possible Environmental Determinants of Juvenile Idiopathic Arthritis).
For several years now, there has been intensive research into the epidemiology and pathogenesis of individual autoimmune diseases. Autoimmune disorders are consistently very complex, and are generally influenced by both genes and the environment.
Interestingly, the incidence of several of these diseases has increased greatly in recent decades, in fact significantly more than would be expected if the cause were purely genetic. This leads to the conclusion that the environment has a considerable influence over the onset of autoimmune diseases.
JIA is an autoimmune disease
This type of close relationship between environmental factors and the onset of disease is suspected to exist for type 1 diabetes (T1D). In juvenile idiopathic arthritis (JIA), a little-researched autoimmune disease of childhood and adolescence, this relationship also seems to play a part. It has been proven that JIA truly is an autoimmune disease and that genetic predisposition plays a decisive role.
As is the case for rheumatoid arthritis (RA), juvenile idiopathic arthritis patients’ synovial membranes contain various inflammatory cells, such as neutrophil granulocytes and dendritic cells. Likewise, a large number of activated T helper cells can be detected, which is also typical of other autoimmune disorders like rheumatoid arthritis, inflammatory bowel disease (IBD), or “juvenile” type 1 diabetes (T1D).
The other components of the immune system are also involved in juvenile idiopathic arthritis. A large proportion of children with JIA thus have detectable antinuclear antibodies (ANA) in their blood serum, as well as rheumatoid factors (RF). The large number of neutrophil granulocytes in the synovial fluid of affected children and the increased concentration of inflammation-mediating cytokines indicate that the inborn immune system is involved in the disease process.
Twin and sibling studies
Twin and sibling studies unequivocally demonstrate that a significant genetic component lies at the root of juvenile idiopathic arthritis. If one identical twin has the disease, the second has a 25 to 40% chance of also having JIA. In comparison, the prevalence of JIA in the normal population (in children under 16 years) is in the range of 1 to 4 children per 1000.
For “singleton” children, the risk of having the disease is significantly higher if a brother or sister suffers from JIA, by a factor of 15 to 30. Computer-assisted analyses also demonstrate that there are several “clusters” of children with JIA who can trace their lines to common ancestors.
Environment has a large influence
Although genes are important to the onset of JIA, certain environmental factors also seem to make a not-insubstantial contribution to the pathogenesis of this autoimmune disease. Truly meaningful studies of the relationship between juvenile idiopathic arthritis and specific environmental influences remain rare. There are frequently not enough subjects in the studies to give them statistical weight, and often the study is designed in a way that does not meet strict scientific guidelines for other reasons.
Breast milk for the immune system
Nursing generally promotes the proper development of the paediatric immune system. Mother’s milk transfers cytokines and other components of the maternal immune system, which influence the immune system of the infant, as described by Justine E. Ellis and co-workers in their review in the journal Rheumatology. In this way, the child can “benefit from the mother’s immunological memory”. This, continue the authors, supports the imprinting and proper maturation of the child’s immune system. Other authors had previously described that incorrect programming of the immune system may generally lead to an increased risk for immune system diseases, as well as autoimmune disorders.
There is currently insufficient data on the influence of nursing on the risk of JIA. However, it is certain that nursing at the mother’s breast offers some protection from juvenile idiopathic arthritis.
Infections and JIA – protection or risk?
Studies have demonstrated a relationship between infections and the risk of developing JIA. The underlying mechanisms for this remain speculative at this time.
One of the much-discussed models is molecular mimicry. It is hypothesized that similarities between the protein structures of pathogens and the body’s own tissues trigger a cross-reaction of the immune system. The proper and regular immune response to bacterial or viral agents jumps over to the tissues and causes the immune system to spin out of control. This results in autoimmune disease.
Another model that attempts to explain the onset of autoimmune diseases through infection is the polyclonal stimulation model. The thought in this case is that lymphocytes are non-specifically activated as a result of an inflammatory reaction. This process could also cause an autoimmune disease.
Hygiene hypothesis: Do infections protect against autoimmune diseases?
There are some indications that childhood infections (especially those in the early years) may reduce the risk of autoimmune diseases in general.
A possible explanation for this is provided by the hygiene hypothesis. This hypothesis was first formulated in 1989 to explain the emergence of allergies. It proposes that a certain exposure to pathogens is required for the proper imprinting and maturation of the immune system of the child; otherwise the risk of allergies is increased.
This hypothesis was later expanded to include the triggering of autoimmune diseases. In a more recent study published in 2005, Jean-Francois Bach describes how the absence of this early exposure or insufficient programming of the immune system can also lead to autoimmune disease subsequent to an infection. Whether childhood infections particularly reduce the risk of juvenile idiopathic arthritis has not yet been sufficiently investigated.
The hygiene hypothesis is also often applied to explain why urban children, only children, or children from more affluent families seem to have a higher risk of getting JIA. It is thought that in these cases it may be possible that the better hygiene in such families prevents the protective effect of early childhood infectious diseases.
Maternal cigarette consumption increases the risk of JIA
The relationship between smoking and rheumatoid arthritis (RA) in adults is proven (see blog Arthritis Support Boardby Dr. S.M. Akerkar). It thus seems obvious to assume a similar connection between a mother’s cigarette consumption in pregnancy and later juvenile idiopathic arthritis (JIA) in the child. Although the few studies on this subject provide some indications of such a relationship, scientific proof has not yet been provided.
What is the role of vitamin D?
There have now been a number of indications that the hormone vitamin D can reduce both the activity of autoimmune diseases and their severity. It has also been demonstrated that vitamin D reduces the risk of developing certain autoimmune disorders. This connection was confirmed for rheumatoid arthritis (RA) and type 1 diabetes (T1D), among others.
How the vitamin D hormone influences the immune system is currently the subject of intensive research. It is known that the active form of the hormone, 1,25-dihydroxyvitamin D3, has a direct influence on the immune system, for example by influencing the differentiation and maturation of dendritic cells to antigen-presenting cells.
Vitamin D also participates in the control of T cells, in that it reduces the production of cytokines IL-12 in Th1 cells. For multiple sclerosis (MS), type 1 diabetes (T1D), and rheumatoid arthritis (RA), it is known that Th1 cells participate in the autoimmune process. It is thus not unrealistic to assume that a similar mechanism applies to the pathophysiology of juvenile idiopathic arthritis.
Overall, the significance of vitamin D to the pathophysiology of JIA is poorly researched. However, it is known from treatment of adult RA patients that vitamin D supplementation can reduce pain and disease activity. Administration of larger doses of the vitamin also reduces the serum concentration of some inflammation markers, such as C reactive protein (CRP).
Because vitamin D can also activate regulatory T-cells, the hormone may have general influence over the development of self-tolerance in the immune system in addition to its modulation of immune response.
Author of this article: Tobias Stolzenberg
Bach JF. Infections and Autoimmune Diseases. J Autoimmun 2005;25 Suppl:74-80 – doi:10.1016/j.jaut.2005.09.024 – LinkOut to the abstract
Ellis JA, Munro JE, Ponsonby AL. Possible Environmental Determinants of Juvenile Idiopathic Arthritis. Rheumatology (Oxford). 2010 Mar;49(3):411-25. – doi:10.1093/rheumatology/kep383 – LinkOut to the abstract
Prahalad S and Glass DN. A Comprehensive Review of the Genetics of Juvenile Idiopathic Arthritis. Pediatr Rheumatol 2008;6:11 – doi: 10.1186/1546-0096-6-11 – open access, free full text
Strachan DP. Hay Fever, Hygiene, and Household Size. Br Med J 1989;299:1259-60 – LinkOut to free full text
Sugiyama D, Nishimura K, Tamaki K, Tsuji G, Nakazawa T, Morinobu A, Kumagai S. Impact of Smoking is a Risk Factor for Developing Rheumatoid Arthritis: a Meta-Analysis of Observational Studies. Ann Rheum Dis 2010;69(1):70-81 – doi:10.1136/ard.2008.096487 – LinkOut to the abstract