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Keywords:

  • autoimmunity;
  • B cell;
  • B cell activating factor of the tumour necrosis factor (TNF) family (BAFF);
  • indigenous Australian;
  • innate immunity;
  • systemic lupus erythematosus (SLE)

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Health status of Indigenous Australians
  5. SLE in Indigenous Australians
  6. Other autoimmune diseases in Indigenous Australians
  7. Infections in Indigenous Australians
  8. Innate immunity, autoimmunity and SLE in Indigenous Australians
  9. Conclusion
  10. References

The incidence and prevalence of autoimmune diseases such as rheumatoid arthritis, primary Sjögren syndrome, scleroderma and systemic lupus erythematosus (SLE) varies with geography and ethnicity. For example, SLE is reported to be more common in populations such as African-Caribbeans and Indigenous Australians (IA). As well as socio-economic status, variation in severity of disease may also show ethnic variability. The initial presentation of SLE in IA, in the context of a unique genetic background and distinctive environmental influences, is often florid with a recurring spectrum of clinical phenotypes. These clinical observations suggest a unique pathway for autoimmunity pathogenesis in this population. For instance, the high prevalence of bacterial infections in IA, particularly group A streptococcus, may be a potential explanation not only for increased incidence and prevalence of SLE but also the commonly florid acute disease presentation and propensity for rapidly progressive end organ threatening disease. This article will review the state of research in autoimmune disease of IA, consider key findings related to autoimmune disease in this population and propose a model potentially to explain the involvement of innate immunity and chronic infection in autoimmune disease pathogenesis. Ultimately, understanding of SLE at this level could affect management and result in personalised and targeted therapies to improve the health status of IA as well as better understanding of SLE pathogenesis per se.


Abbreviations
ANA

anti-nuclear autoantibody

ANCA

anti-neutrophil cytoplasmic antibody

ARF

acute rheumatic fever

BAFF

B cell activating factor of the tumour necrosis factor family

BLyS

B lymphocyte stimulator

CR1

complement receptor 1

dsDNA

double stranded deoxyribonucleic acid

Fc

fragment crystallisable

GAS

group A streptococcus

IA

indigenous Australians

IFN

interferon

MHC

major histocompatibility complex

MPO

myeloperoxidase

NATSIHS

National Aboriginal and Torres Strait Islander Health Survey

NZB

New-Zealand black

NZW

New-Zealand white

PBMC

peripheral blood mononuclear cell

pDC

plasmacytoid dendritic cell

PR3

proteinase 3

RA

rheumatoid arthritis

RNA

ribonucleic acid

RNP

ribonucleoprotein

SES

socio-economic status

SLE

systemic lupus erythematosus

Sm

Smith

TLR

toll-like receptor

TNF

tumour necrosis factor

UVR

ultraviolet radiation

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Health status of Indigenous Australians
  5. SLE in Indigenous Australians
  6. Other autoimmune diseases in Indigenous Australians
  7. Infections in Indigenous Australians
  8. Innate immunity, autoimmunity and SLE in Indigenous Australians
  9. Conclusion
  10. References

It is well recognised that geography and ethnicity can affect the incidence and prevalence of diseases such as rheumatoid arthritis (RA),[1, 2] primary Sjögren's syndrome,[1, 3, 4] scleroderma[5] and systemic lupus erythematosus (SLE).[6] SLE prevalence is higher among African-Americans,[7] African-Caribbeans,[8, 9] Hispanics,[7] Asians,[8, 10] North American Indians[11] and Indigenous Australians (IA).[12-16] Differences in socio-economic status (SES) do not explain the increased frequency of lupus nephritis in African-Caribbean patients,[17] and are less important than genetic factors to explain ethnic disparity in lupus nephritis.[18] Although the current underprivileged SES of IA has a negative impact on quality of life, the effect of SES on SLE in IA is unknown. In contrast, in SLE, ethnic variations have been reported affecting disease severity and resistance to therapy,[19] including in studies in urban Australia.[20]

IA have distinctive customs, traditions, legacies, socio-economic and health characteristics. Unfortunately, they remain disadvantaged socio-economically, in health outcomes and life expectancy compared with other Australians, despite ongoing endeavours to correct these discrepancies. IA are a unique population globally, and investigation of their autoimmune disease expression in terms of incidence, prevalence and phenotype may reveal distinct pathways for the pathogenesis of autoimmune diseases. In the IA population, bacterial infections, especially group A streptococcus (GAS), are very common and frequently chronic.[21] The high prevalence of infection in IA may contribute not only to disease susceptibility but also to phenotypic disparities of autoimmune disease, through involvement of innate immune pathways. Interactions between genetic and environmental factors rather than genetics alone may be implicated in variations in disease expression in IA, and increased understanding may lead to better knowledge of autoimmune disease pathophysiology, encourage the development of targeted therapies designed to modulate the innate immune system, and improve the health status of IA.

Health status of Indigenous Australians

  1. Top of page
  2. Abstract
  3. Introduction
  4. Health status of Indigenous Australians
  5. SLE in Indigenous Australians
  6. Other autoimmune diseases in Indigenous Australians
  7. Infections in Indigenous Australians
  8. Innate immunity, autoimmunity and SLE in Indigenous Australians
  9. Conclusion
  10. References

In the 2006 Australian census, the IA (Aboriginal and Torres Strait Islander) population of 517 000 people accounted for nearly 2.5% of the total population.[22] In North Queensland, the Northern Territory and the northern parts of South Australia and Western Australia, IA can make up to 30% of the population with nearly 50% of these people living in non-urban settings. The median age of IA was 21 compared with 37 for non-Indigenous Australians (non-IA). Compared with other Australians, IA often live in impoverished circumstances, and are more at risk of suffering disability and reduced health-related quality of life from chronic illness or trauma. Perinatal mortality is high, and IA have higher mortality rates for all age groups compared with the general population. In the period 2005–2007, life expectancy at birth for male IA was 67.2 years, 72.9 years for women, 11.5 and 9.7 years less respectively than the national average. Tobacco smoking, excessive alcohol consumption and other substance abuse, obesity, road trauma, domestic violence, poor nutrition and limited access to or suboptimal utilisation of health services, all contribute to increased morbidity and mortality in IA.[23]

SLE in Indigenous Australians

  1. Top of page
  2. Abstract
  3. Introduction
  4. Health status of Indigenous Australians
  5. SLE in Indigenous Australians
  6. Other autoimmune diseases in Indigenous Australians
  7. Infections in Indigenous Australians
  8. Innate immunity, autoimmunity and SLE in Indigenous Australians
  9. Conclusion
  10. References

SLE is a chronic inflammatory systemic autoimmune disorder, characterised by multiple organ and tissue damage, particularly joints, the heart, lungs, skin and kidneys. SLE follows a relapsing and remitting course and occurs at a 9:1 female to male ratio. SLE results in considerable morbidity, mortality, disability and poor health-related quality of life.[24] Social and/or family disruption are also common sequelae of SLE as young women of child-bearing age are the most commonly affected demographic. One of the hallmarks of SLE is the production by autoreactive B -lymphocytes of autoantibodies with specificity for a wide range of self-antigens, especially a spectrum of nuclear and cytoplasmic antigens. These include anti-nuclear autoantibodies (ANA), as well as some subtypes of ANA highly specific for SLE, such as anti-double stranded deoxyribonucleic acid (dsDNA) and anti-Smith antibodies.[24] Pathogenic autoantibodies play a critical role in many SLE clinical manifestations including autoimmune haemolytic anaemia, thrombocytopenia, antiphospholipid antibody syndrome, cutaneous lupus and foetal heart block in neonatal lupus. Complement activation, and engagement of fragment crystallisable receptor and complement receptors, such as complement receptor 1, are associated with certain SLE clinical lesions such as glomerulonephritis.[25]

The aetiology of SLE is thought to be multifactorial, and includes environmental and genetic factors. Compared with Caucasians, the prevalence of SLE is higher among North American Indians, African-Americans, African-Caribbeans, Hispanics and Asians.[8-11, 19, 26-30] In IA, the reported prevalence of SLE varies from 52.6 to 92.8 per 100 000 people, a prevalence two to four times higher than that of Caucasians (Table 1).[12-16] In Far North Queensland, SLE prevalence in IA was 92.8 per 100 000 persons, twice that of the generally European descended population (45.3 per 100 000 persons).[13] In the Northern Territory, SLE prevalence was estimated at 52.6 per 100 000 in a hospital-based study, at least twice the estimated prevalence, with high mortality and morbidity.[12]

Table 1. SLE prevalence and biological disease phenotypes associations with Indigenous Australians
AreaPrevalence in IAPrevalence in non-IAIA-to-non-IA ratioAnnual incidence in IABiological associationMortality in IAReferences
  1. CA, Central Australia; IA, Indigenous Australians; non-IA, non-Indigenous Australians; NR, non reported; NT, Northern Territory; QLD, Queensland; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; Sm, Smith; WA, Western Australia.

Far North QLD92.8/100 00045.3/100 0002 to 1NR-HighBossingham[13]
NT1:1 900 (52.6 per 100 000)NR2 (to 3) to 111 per 100 000Anti-Sm Abs positively associatedHighAnstey et al[12]
CA1:1 360 (73.5 per 100 000)1:5 170 (19.3 per 100 000)3.8 to 1NR

Lower in IA: anticardiolipin, lupus anti-coagulant

Higher in IA: anti-Sm and anti-RNP, leucopaenia, thrombocytopenia, lymphopenia

Low (but higher than in non-IA)Segasothy et al[15]
WA1:4 500 (22.2 per 100 000)NRNRNRNRHighBloor et al[16]
Far North QLD1:1 120 (89.3 per 100 000)NRNRNRNRNRGrennan et al[14]
Metropolitan Sydney1:7 466 (13.4 per 100 000)

SLE in Indigenous Australians: a distinctive disease phenotype

SLE is severe in IA, with high mortality rates.[12, 13, 16] For example, the incidence of end-stage renal disease due to lupus nephritis is 2.83 times higher in IA compared with non-IA.[31] In Far North Queensland, SLE was found to be more severe with a shorter disease duration and a high mortality, a lower rate of photosensitivity but a higher rate of nephritis.[13] In this study, there were no differences between IA and non-IA regarding autoantibodies. In the Northern Territory, IA exhibited a higher prevalence of lupus nephritis, with 62% of patients exhibiting significant proteinuria, and anti-Smith autoantibodies were more commonly detected.[12] In a study in Central Australia, anti-Smith and anti-ribonucleoprotein antibodies, leucopenia, lymphopenia, and thrombocytopenia were higher in IA, whereas anticardiolipin and the presence of lupus anti-coagulant were less frequent compared with non-IA.[15] In this study, IA were more likely to show fever and pneumonitis but exhibited less malar and discoid rash, photosensitivity, oral ulcer or pleuritis, compared with non-IA. Mortality was higher than in non-IA.[15] In a unique study of an IA family living in Far North Queensland, among 92 identified family members, five had SLE, and 10 others had other autoimmune diseases, without any clear Mendelian pattern of inheritance.[32]

Even if the high mortality and morbidity of SLE in IA are contributed to by late presentation and poor therapy adherence, the prevalence of SLE is still higher than in non-IA, and this is not understood. Interestingly, prevalence, clinical and biological phenotypes of SLE appear not only to be distinctive in IA compared with non-IA but also to differ between IA communities,[14] which may reflect both environmental and genetic factors. Differences in SLE prevalence, biological and clinical phenotypes were reported in a study comparing IA from Northern Queensland and metropolitan Sydney,[14] potentially reflecting differences in environmental factors such as ultraviolet radiation exposure and the prevalence of infection.[13, 32] The higher prevalence of SLE in Northern Territory IA was reported to be associated with a higher occurrence of C4 null alleles,[33] but this was not confirmed in another study.[34] The incomplete penetrance of SLE in one IA family with a 5% prevalence of SLE[32] suggests an interaction between genetic factors promoting an autoimmune susceptibility, and environmental factors, such as skin infections and high ambient ultraviolet radiation exposure, as a trigger.[32] These ‘geo-ethnic’ differences in incidence, prevalence, disease phenotype, severity, treatment resistance and mortality, while highlighting a gap in the understanding of SLE pathogenesis, suggests an alternative approach to SLE pathogenesis with potential implications for autoimmunity in general.

Other autoimmune diseases in Indigenous Australians

  1. Top of page
  2. Abstract
  3. Introduction
  4. Health status of Indigenous Australians
  5. SLE in Indigenous Australians
  6. Other autoimmune diseases in Indigenous Australians
  7. Infections in Indigenous Australians
  8. Innate immunity, autoimmunity and SLE in Indigenous Australians
  9. Conclusion
  10. References

Rheumatoid arthritis

A recent study based on 3220 IA and 15120 non-IA (National Aboriginal and Torres Strait Islander Health Survey), showed a higher prevalence of self-reported RA in IA compared with non-IA.[35] Other studies have suggested a high prevalence of interracial marriage among IA with RA,[36, 37] but in contrast, in a recent unselected population survey, no case of RA was reported in IA.[38] Genetics might explain a low prevalence of RA in IA, as IA rarely harbour the rheumatoid major histocompatibility complex class II shared epitope.[39] It is noteworthy that the carriage of the shared epitope was more frequent in IA of the Kimberley and Cape York, pointing out genetic differences in different regions of Australia.[39, 40]

Spondyloarthropathy and HLA-B27 related diseases

HLA-B27 was reported to be absent[41, 42] or very low prevalence[43] in IA. In a recent study, the prevalence of anterior or posterior uveitis was 0.21 and 0.59%, respectively.[44] Psoriatic arthritis was evaluated in only one survey with a point prevalence of 0.5%,[38] and there are no published data for ankylosing spondylitis or Crohn disease in IA. This does not exclude the possibility of seronegative disease in IA. A study performed in the tropical highlands of Papua New Guinea highlighted that many cases of acute polyarthritis were classified as ‘tropical polyarthritis’ whereas, most patients had an oligoarthritis consistent with a reactive arthritis.[45]

Systemic sclerosis

There is only a reported single case study of systemic sclerosis in IA.[5] After consulting the South Australian Scleroderma Register, the authors found five other cases of systemic sclerosis in IA. This suggests a very low prevalence of scleroderma in IA, a disease in which ethnicity appears to be important for susceptibility, for example among African-Americans and Choctaw Native Americans (reviewed in Zurauskas et al.[5]).

Autoantibodies in Indigenous Australians

In a study in Northern Australia, IA were observed to more frequently exhibit positive ANA, anti-Ro, Ro/La, and ribonucleoprotein antibodies compared with non-IA.[46] Similarly, anti-neutrophil cytoplasmic antibodies were more often detected in IA sera, whereas anti-proteinase 3, anti-myeloperoxidase, anti-endomysial, anti-mitochondrial and anti-centromere antibodies were absent or rarely detected.[46] Personal observations of anti-neutrophil cytoplasmic antibody-related vasculitis and dermatomyositis have been reported in IA.[37] There are no published data on the prevalence of primary Sjögren Syndrome, autoimmune thyroiditis, coeliac disease, vitiligo or psoriasis in IA.

Infections in Indigenous Australians

  1. Top of page
  2. Abstract
  3. Introduction
  4. Health status of Indigenous Australians
  5. SLE in Indigenous Australians
  6. Other autoimmune diseases in Indigenous Australians
  7. Infections in Indigenous Australians
  8. Innate immunity, autoimmunity and SLE in Indigenous Australians
  9. Conclusion
  10. References

Skin infections, especially fungal and bacterial infection of insect bites,[13] are very common and chronic among IA.[21] There is a high prevalence of major bacterial infection in North Queensland, particularly GAS infections, and a high prevalence of post-infectious sequelae such as acute rheumatic fever (ARF).[14] IA children of central and northern Australia exhibit the highest rates of ARF in the world (245–500 per 100 000 persons).[47, 48]

GAS diseases include mild infection, such as pharyngitis, pyoderma, impetigo, more invasive infections such as necrotising fasciitis, and also post-streptococcal sequelae such as acute post-streptococcal glomerulonephritis and ARF. ARF is a post-infectious systemic autoimmune disease triggered by previous GAS infection. ARF is caused by an abnormal immune response to specific bacterial epitopes of GAS, particularly the streptococcal M-protein. Antibody cross-reactivity between GAS epitopes and human tissues may initiate this autoimmune response through molecular mimicry (reviewed in Carapetis et al.[47]). ARF is said to follow GAS pharyngitis but not skin infection, however IA children have a low incidence of GAS pharyngitis and low rates of upper respiratory tract GAS carriage but a high incidence of pyoderma.[49, 50] In high-incidence ARF populations, including IA in the Northern Territory and Maori people in New Zealand, the M-serotypes of GAS are absent. Thus, the role of other serotypes, likely to be involved in skin infection such as GAS impetigo, may be crucial in ARF pathogenesis in these populations (reviewed in Steer et al.[51]). In addition, some specific B cell alloantigens have been reported to be associated with susceptibility to ARF and rheumatic heart disease (reviewed in Carapetis et al.[47]). One study of ARF in IA showed significantly higher levels of antibodies to cardiac autoantigens compared with controls.[52] The similarities between post-GAS auto-immunity, which affects skin, joints, kidneys and brain and SLE, suggest the possibility of GAS as a model for autoimmune disease pathways in IA that may differ from those in other races.

Innate immunity, autoimmunity and SLE in Indigenous Australians

  1. Top of page
  2. Abstract
  3. Introduction
  4. Health status of Indigenous Australians
  5. SLE in Indigenous Australians
  6. Other autoimmune diseases in Indigenous Australians
  7. Infections in Indigenous Australians
  8. Innate immunity, autoimmunity and SLE in Indigenous Australians
  9. Conclusion
  10. References

Activation of innate immunity in autoimmune diseases

For a long time, loss of T cell tolerance has been considered central to the pathogenesis of many autoimmune disorders; however, it is now clear that defective B cell regulation and production of pathogenic autoantibodies play an important role in driving disease. SLE has been associated with dysregulated homeostasis and T cell function in both mice with lupus-like disease[53] and in some SLE patients.[54] However, T cells may not be always critical for the pathogenesis of certain autoimmune diseases such as SLE. It is postulated under these circumstances that stimulation of innate immunity may lead to the development of autoimmunity independent of T cells.[55, 56] Specific intracellular receptors known as Toll-like receptors (TLR) mediate the activation of innate immune responses in response to nucleic acids as represented by infections. Immune complexes containing ribonucleic acid or DNA are able to bind and activate intracellular TLR-7 and TLR-9.[57, 58] These pathways may be operative both in response to infections and in the development of autoimmunity. Increased activation of TLR-7/9 leads to activation of plasmacytoid dendritic cells with resulting production of type I interferons (IFN) which can promote inflammation (reviewed in Ronnblom[59]). Although desirable as part of an anti-microbial response, SLE, as well as primary Sjögren syndrome, are characterised by up-regulated expression of type I IFN and an ‘IFN signature’,[60, 61] suggesting overexpression of genes induced by the type I IFNα.[62] Furthermore, increased expression of TLR-7 and -9 and IFNα in peripheral blood mononuclear cells[63] and increased TLR-9 positive B cells in the blood[64] have been reported in SLE patients. Finally, effective treatment of SLE by anti-malarial drugs is reportedly through inhibition of endosomal TLR-mediated signalling, such as TLR-7 and TLR-9.[65] These data suggest a pathway through which infectious activation of innate immune responses and responses to self-antigens derived from the nucleus overlap.

B cell activating factor of the tumour necrosis factor family (BAFF), innate immunity and autoimmune disease

The cytokine B cell activating factor of the tumour necrosis factor family (BAFF; also known as B lymphocyte stimulator, TNFSF13B, THANK, TALL-1 and zTNF4)[6] may represent a molecular link between innate immunity and autoimmune responses. TLR-induced type I IFN enhances BAFF production by DC.[66] Importantly, BAFF in turn enhances TLR-7/9 expression in B cells and TLR-induced autoantibodies production,[55] suggesting a positive feedback loop in the presence of TLR activation. BAFF is required for the survival of both transitional and mature B cells,[67] and high BAFF levels may lead to increased survival of autoreactive cells and class switching from IgM to IgG.[55] Two strains of lupus-prone mice (MRL-lpr/lpr and New-Zealand black x New-Zealand white (NZBxNZW)F1) have also been reported to have elevated BAFF levels, and to show improvement in disease manifestations in response to inhibition of BAFF.[68] Transgenic mice that overexpress BAFF develop a SLE-like syndrome with B cell hyperplasia, enlargement of the spleen and lymph nodes, elevated serum levels of anti-dsDNA antibodies and rheumatoid factor, hypergammaglobulinaemia, circulating immune complexes and glomerulonephritis with proteinuria and immunoglobulin deposits.[69]

Elevated levels of serum BAFF have been detected in a proportion of SLE patients, as well as in other autoimmune diseases such as RA, primary Sjögren syndrome, immune thrombocytopenia, multiple sclerosis, bullous pemphigoid and systemic sclerosis. Although these levels are reported to be associated with autoantibody levels and SLE activity in some studies, this association has not been confirmed in other studies (reviewed in Vincent et al.[6]). Successful results in SLE of two phase III clinical trials of belimumab, an anti-BAFF monoclonal antibody,[70, 71] confirm the importance of the BAFF system in SLE pathogenesis. Strikingly, SLE patients lacking autoantibodies in significant titre are less likely to respond to belimumab.[72]

Importantly, BAFF-transgenic mice develop features of SLE both in the presence and absence of T cells,[55] suggesting BAFF as a mediator of T cell-independent autoimmunity that could be relevant to the autoimmunity observed in populations with high rates of infection. Notably, no data on BAFF expression or function in IA SLE have been reported.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Health status of Indigenous Australians
  5. SLE in Indigenous Australians
  6. Other autoimmune diseases in Indigenous Australians
  7. Infections in Indigenous Australians
  8. Innate immunity, autoimmunity and SLE in Indigenous Australians
  9. Conclusion
  10. References

The incidence, prevalence and disease phenotype of autoimmune diseases in IA differ markedly from that observed in non-IA, suggesting the possibility of distinct pathogenic pathways in these individuals. Powerful socio-economic factors, a distinct genetic background and a higher prevalence of infections in IA might lead to hyper-stimulation of innate immunity through TLR, which in turn may lead to IFN and BAFF system dysregulation, with abnormal activation of B cells and autoimmunity as a consequence. The role of BAFF/innateimmunity interactions in SLE in IA, and the impact of specific environmental factors such as GAS, remains to be determined; but if demonstrated, this would reveal a new paradigm for the causation of SLE.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Health status of Indigenous Australians
  5. SLE in Indigenous Australians
  6. Other autoimmune diseases in Indigenous Australians
  7. Infections in Indigenous Australians
  8. Innate immunity, autoimmunity and SLE in Indigenous Australians
  9. Conclusion
  10. References