Biennial Report of the Director

Research in Diseases, Disorders, and Health Conditions
Autoimmune Diseases

Autoimmune diseases are a group of more than 80 chronic and often rare illnesses due in part to an inappropriate immune system response that leads the body to attack its own organs, tissues, and cells. Some of these diseases may be triggered by an infectious agent or an environmental exposure, especially in individuals who have inherited susceptibility. In the U.S., between 14.7 and 23.5 million individuals are affected by autoimmune diseases, with women disproportionately affected. An estimated 75 percent of rheumatoid arthritis (RA) cases are women; systemic lupus erythematosus (SLE or lupus) afflicts African American women four times more often than Caucasian women; and Caucasians are more than twice as likely as other races to develop multiple sclerosis (MS) and, in general, women are affected with MS at almost twice the rate of men.

NIH recognizes that more needs to be done to close the gaps in knowledge and reduce the rising impact of autoimmune diseases. NIH is committed to advancing the understanding of how autoimmune diseases develop and to applying results of basic research to improve the health and quality of life of patients affected with these diseases.

The most common of these diseases include systemic lupus erythematosus (SLE), MS, type 1 diabetes, autoimmune thyroid diseases, myasthenia gravis, scleroderma, inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis, and RA. Organ-specific autoimmune diseases are characterized by immune-mediated injury localized to a single organ or tissue, for example, the pancreas in type 1 diabetes and the central nervous system in MS. In contrast, nonorgan-specific diseases, such as SLE, are characterized by immune reactions against many different organs and tissues, which may result in widespread injury.

Autoimmune diseases can affect any part of the body and have myriad clinical manifestations that can be difficult to diagnose. Genetic traits may enhance susceptibility to many of these diseases, so that a patient may suffer from more than one autoimmune disorder, or multiple autoimmune diseases may occur in the same family. Furthermore, scientists suspect that hormones may play a role in the development of at least some autoimmune disorders. For these and other reasons, autoimmune diseases are best recognized as a family of related disorders that must be studied together as well as individually.

Although treatments are available for numerous autoimmune diseases, cures have yet to be discovered and patients face a lifetime of illness and treatment. They often endure debilitating symptoms, loss of organ function, and hospitalization. The social and financial burden of these diseases is immense and includes poor quality of life, high health care costs, and substantial loss of productivity.

NIH supports research and promotes progress toward conquering autoimmune diseases through a wide range of research projects and programs. Because autoimmune diseases span many organ systems and clinical disciplines, multiple NIH Institutes conduct and support autoimmune disease research, often in collaboration with professional and patient advocacy organizations. The congressionally mandated Autoimmune Diseases Coordinating Committee (ADCC), chaired by NIAID, facilitates trans-Institute collaboration and cooperation with twice yearly meetings devoted to discussion of autoimmune diseases research programs.

NIH Funding for Autoimmune Disease Research

NIH funding for autoimmune diseases research was $856 million in FY 2010, and $869 million in FY 2011 for non-ARRA (regular appropriations) and $125 million in FY 2010 for ARRA appropriations.273

Summary of NIH Activities

Collectively, NIH-funded research seeks to understand the onset and progression of over 80 types of autoimmune diseases and to use that knowledge to develop better strategies for disease prevention, diagnosis, and treatment. Research on these diseases is funded by a number of ICs.

NIAID-supported research on autoimmune diseases focuses on the immunologic basis of disease, including the fundamental immunologic principles underlying disease onset and progression, developing improved animal models of disease and diagnostic tools, and identification and evaluation of more effective immune-based treatments and prevention strategies.

Nine NIAID Autoimmunity Centers of Excellence (co-sponsored by ORWH) conduct collaborative research including clinical trials of immunomodulatory therapies and mechanistic studies, and enable partnerships among clinicians and basic researchers. Their goal is to facilitate the identification of effective tolerance induction and immune modulation strategies to prevent or treat disease and accelerate the translation of scientific advances to the clinic. Research at the Centers focuses on lupus, Sjögren’s syndrome, rheumatoid arthritis, MS, ulcerative colitis, scleroderma, pemphigus vulgaris, and type 1 diabetes. Two clinical trials were recently completed for treatment of pemphigus with infliximab and for treatment of Sjögren’s with Rituximab. The Centers have also published several articles that provide more detailed understanding of the tublointestinal inflammation in human lupus, and human regulatory T cells (Tregs) in healthy subjects and those with type 1 diabetes, findings that one day may lead to better treatments.

The NIAID Immune Tolerance Network (ITN) evaluates novel, tolerance-inducing therapies for autoimmune diseases, conducts mechanistic studies to understand the cause of tolerance, and develops and evaluates markers and assays to measure the induction, maintenance, and loss of tolerance in autoimmunity. Results from a recent ITN study showed that treatment with intravenous rituximab and steroids for patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis produced the same outcome as the treatment that has been used for more than 40 years. However, the new treatment regimen requires a much shorter treatment duration and early results suggest that the regimen elicits better response in patients with disease relapses.

The Cooperative Study Group for Autoimmune Disease Prevention (CSGADP) conducts research on the development of new therapeutic targets and approaches to prevent autoimmune diseases (co-sponsors: NIDDK and JDRF). In 2010, CSGADP supported 21 pilot projects that may lead to the development of novel targets for disease prevention or assays for biological markers of disease progression. CSGADP will be renewed in fiscal year 2012.

The HLA Region Genomics in Immune-Mediated Diseases Consortium is a cooperative research group that focuses on defining the association between variations in the human leukocyte antigen (HLA) genetic region and immune-mediated diseases including autoimmune diseases (co-sponsor: NINDS). NIAID continues to support two trials to evaluate autologous hematopoietic stem cell transplantation for the treatment of scleroderma and MS, including mechanistic studies of these diseases and therapies.

In the NIAID intramural research program (IRP), scientists are conducting investigations of biological pathways that may be common to many autoimmune diseases, yielding fundamental information that will guide the development of novel therapies for these diseases. NIAID investigators also are exploring genetic and environmental factors, including infection, that affect the development of autoimmune diseases. Examples of NIAID IRP research include:

NIDDK funds a wide range of research on type 1 diabetes, inflammatory bowel diseases, celiac disease, and other autoimmune diseases. For example, Type 1 Diabetes TrialNet is an international network of researchers who are exploring ways to prevent, delay, and reverse the progression of type 1 diabetes. TrialNet screens large numbers of individuals and conducts trials of agents to prevent type 1 diabetes in at-risk people and to slow progression of the disease in people who are newly diagnosed. The Environmental Determinants of Diabetes in Youth (TEDDY) study has completed enrollment of over 8,000 high-risk newborns and is collecting biosamples for analysis to identify potential triggers of type 1 diabetes. Identification of an infectious agent that triggers autoimmunity could lead to a vaccine to protect against type 1 diabetes. Or, if dietary factors are identified that protect from or contribute to development of the disease, changes to infant feeding practices could be recommended.

The NIDDK Inflammatory Bowel Disease (IBD) Genetics Consortium is a major driver of the Institute’s IBD research program. The Consortium provides support and resources to enhance gene discovery and uncover the role that genetics plays in these complex diseases. For example, the Consortium has used genome-wide association studies of adult and pediatric populations over the past several years to uncover several genetic variants associated with ulcerative colitis and Crohn’s disease.

NIDCR conducts research on Sjögren’s Syndrome, a chronic autoimmune disease in which white blood cells attack the body’s own salivary and tear glands, decreasing production of saliva and tears and resulting in significant oral and ocular disease and discomfort. NIDCR’s Sjögren’s Syndrome Clinic is part of the Molecular Physiology and Therapeutics Branch in NIDCR. The mission of the Clinic is to develop new therapies based on better understanding of the pathogenesis of this disease. The Clinic designs studies to address unmet clinical needs, bridge traditional medical specialties, and fosters close collaboration between clinical and basic scientists.

The International Sjögren’s Syndrome Registry is funded by NIDCR, NEI, and ORWH. The goal of the registry is to promote research on Sjögren's syndrome, with an emphasis on diagnosis, epidemiology, causes, prevention, and treatment.
A number of research efforts are underway examining the potential role of a number of different microRNAs in Sjögren's syndrome. A microRNA is a very short piece of RNA found in the cells of plants, animals, and humans. MicroRNAs are key orchestrators of genome functions in both normal development and in disease. Investigators are examining how microRNA expression affects salivary flow, as well as using microRNA expression profiles as biomarkers of salivary gland inflammation in Sjögren's syndrome. Two microRNAs have been validated as markers of inflammation and researchers are in the process of creating a standardized assay for examination of those markers in a larger clinical cohort. Additionally, a large-scale effort is underway to determine the global expression of microRNAs and other non-coding short RNAs present in salivary secretions and salivary glands in Sjögren’s syndrome patients and healthy volunteers. The research data are expected to be of considerable use in allowing the development of diagnostic and disease progression biomarkers that can reflect the physiological status of the salivary gland without the need of a biopsy and invasive procedures.

NIDCR’s current active clinical protocols include:

Because autoimmune disorders disproportionately affect girls and women, ORWH has had a lengthy record of research support for these conditions, and has partnered across the NIH ICs.

Some of the FY 2011 grants focus on specific autoimmune disorders such as MS, RA, or SLE. ORWH has also contributed continuously to the Autoimmune Centers of Excellence, which support clinical trials and basic research on new immune-based therapies for a variety of autoimmune disorders. In FY 2011, ORWH supported several innovative areas of study, such as predictors of pregnancy outcome in SLE and antiphospholipid syndrome, and the study of a new molecular pathway which is likely to be important in the pathogenesis and treatment of MS.

In FY 2010, investigators made a major clinical advance in treating people with a severe form of vasculitis known as anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, a rare but devastating disease of blood vessels. In FY 2011, based on the results of an ITN Phase II/III clinical trial, the FDA approved rituximab in combination with glucocorticoids to treat patients with Wegener’s granulomatosis and microscopic polyangiitis, two rare forms of autoimmune disorders that affect small blood vessels in kidney, lung, sinuses, and a variety of other organs. This is the first FDA-approved treatment for these rare and relapsing diseases.274

Several research groups have demonstrated that induced specialized immune cells known as inducible regulatory T cells have less stability in vivo than natural regulatory T cells and that inducible regulatory T cells may actually develop into effector T cells that can cause autoimmune disease. Effector T cells are responsible for most of the cellular immune responses against invading pathogens and certain malignancies. NIAID scientists have conducted pre-clinical studies that emphasize the need for characterizing inducible regulatory T cells, as these cells interact with immune molecules and can affect proteins involved in immune system response. By understanding more about inducible regulatory T cells, scientists may one day be able to manipulate these cells to treat human autoimmune disease.275

Researchers, including those in NIDDK’s IBD Genetics Consortium, identified 30 new genetic regions associated with Crohn’s disease, doubling the number of associated genetic variants.276 In a separate study, 29 new genetic variants that increase the risk for ulcerative colitis were identified. Based on these analyses, the total number of identified IBD risk loci has increased to 99, with 28 genetic variants in common between ulcerative colitis and Crohn’s disease.277 Finding new genetic variants will help scientists discover the molecular pathways that contribute to these diseases and can lead to new therapeutic targets.

In NIDDK-sponsored research on a mouse model of celiac disease, when the mice were fed gliadin, a component of the dietary protein gluten, the inappropriate intestinal immune reaction that is mounted against the gliadin was further promoted by feeding retinoic acid, a form of vitamin A, to the animals. Therefore, in this context, retinoic acid further enhances inappropriate immune responses, rather than protecting against them as it does in other immunological settings. This study yielded a new animal model of early-stage celiac disease to enable future research, and warns against using vitamin A or retinoic acid as a treatment for patients with celiac disease.278

Pathogenic T helper cells are an important factor in many autoimmune diseases. For example, stimulation of the receptor for the signaling lipid sphingosine-1-phosphate (S1P1) simultaneously produces proinflammatory and anti-inflammatory effects. S1P1 acts through the enzyme mTOR, which is targeted by two immunosuppressive drugs—rapamycin, which is used to prevent transplant rejections, and FTY720, a promising oral therapy for MS. These drugs have been shown to regulate the balance between inflammatory T helper 1 and suppressive T regulatory cells, and provide new insights into autoimmune disease pathogenesis, and potential therapeutic strategies.279

Recent research indicates that three proinflammatory cytokines—interleukin-6 (IL-6), IL-1ß, and IL 23—are sufficient to induce T helper 17 cell differentiation in a mouse model. Inducing T helper 17 cell differentiation can cause severe autoimmune disease, as the cells are involved in inflammation and tissue damage. The research shows that transforming growth factor ß—previously thought to be essential—is not critical to T helper 17 cell formation. These findings provide new insights into the factors in autoimmunity, and possibilities for targeted therapies.280

Interferon regulatory factor 5 (IRF5) regulates the activity of type 1 interferons and other proinflammatory cytokines during viral infections and in some autoimmune diseases, and polymorphisms in the IRF5 gene have been associated with several autoimmune rheumatic diseases. In a model of inflammation, histone deacetylases and histone acetytransferases alter the IRF5 protein, causing increased inflammation. Thus, IRF5 regulates inflammation in conjunction with histone deacetylases and histone acetyltransferases. Understanding how IRF5, histone deacetylases, and histone acetyltransferases mediate inflammation could inform therapeutic strategies for treating autoimmune diseases.281

273   For funding of various Research, Condition, and Disease Categories (RCDC), see https://report.nih.gov/categorical_spending.aspx.
274 Stone JH, et al. N Engl J Med. 2010;363(3):221–32. PMID: 20647199.
275 Chen Q, et al. J Immunol. 2011;186(11):6329–37. PMID: 21525380.
276 For more information, see https://www.nature.com/ng/journal/v42/n12/full/ng.717.html Exit Disclaimer.
277 For more information, see https://www.nature.com/ng/journal/v43/n3/full/ng.764.html Exit Disclaimer.
278 For more information, see https://www.nature.com/nature/journal/v471/n7337/full/nature09849.html Exit Disclaimer.
279 For more information, see https://www.nature.com/ni/journal/v11/n11/full/ni.1939.html Exit Disclaimer.
280 For more information, see https://www.nature.com/nature/journal/v467/n7318/full/nature09447.html Exit Disclaimer.

281 For more information, see https://www.jimmunol.org/content/185/10/6003.long Exit Disclaimer.

A comprehensive map of specific and unique microRNA “signatures” from a variety of lymphocytes provides new understanding of epigenetic regulation of microRNA expression during lymphocyte development, differentiation, and in the immune response. MicroRNAs are key orchestrators of how the genome functions. These insights into mechanisms of how immune cells regulate internal conditions to maintain health and function and the immune response will support further investigations in immune dysfunction and autoimmunity.

Uveitis is a collection of acute and chronic vision-threatening conditions with various causes, but all resulting in inflammation in the eye. In 2010, the NEI-funded Standardization of Uveitis Nomenclature Working Group achieved consensus on clinical grading of ocular inflammation and standardization of research reporting, which facilitated meta-analyses across standardized clinical studies and provides a common language to describe inflammatory conditions. In autoimmune diseases, the T cells, which normally function to attack microbes start to attack the body’s own cells, often by releasing chemical messages called interleukins. Regulatory T cells combat these autoreactive T cells waging chemical warfare by releasing protective interleukins. One recently identified type of helper T cell (Th17) has emerged as a key factor in the pathogenesis of ocular inflammation. A robust experimental model of autoimmune uveitis helped resolve the complex roles of Th17 cells, interleukin 21, and other helper and regulatory T cells. Autoimmune uveitis is currently treated with corticosteroids and sometimes systemic immunosuppression, although this research shows that blocking specific interleukins may be sufficient in the future. In 2011, the first large randomized clinical trial comparing current uveitis treatments provided important information on treatment outcomes of different regimens.

 For the mouse embryonic salivary gland, NIDCR investigators recently demonstrated282 that stimulation by the cholinergic parasympathetic nerves is required for maintenance of rare cells that circulate in the blood with the ability to differentiate into cells that make up the lining of blood vessels. Their finding may signal new ways to regenerate salivary glands in patients who have lost salivary gland function, and suggests that nerve-dependent organ regeneration is relevant to the growth and regeneration of other organ systems.

Identified genes regulating the formation of the branched epithelial structures were found in multiple organ systems including lungs, mammary, and salivary glands, indicating that temporary loss of cell-cell interactions enables formation and propagation of clefts within sheets of cells283. These researchers were able to show that in mice, these genes were involved in both mammalian salivary gland and lung branching morphogenesis, suggesting this conserved process could be important in efforts to regenerate functional salivary glands and other branched organs.

 NIDCD-funded scientists recently explained how glucocorticoids, a commonly prescribed family of drugs to treat hearing loss related to autoimmune diseases such as lupus and rheumatoid arthritis, do not work on inflammation as previously thought, but appear to correct an imbalance in ions in the fluid of the inner ear. The research team hypothesizes that developing a treatment based on regulating ion concentration, instead of controlling inflammation, may be more effective and offer fewer side effects than steroids for people with autoimmune-related hearing loss.284

Autoimmune sensorineural hearing loss (ASNHL) is caused by the body attacking and destroying its own sound-detecting and balance-maintaining tissues in the inner ear. Although this produces progressive hearing loss and/or dizziness in both ears, it is potentially reversible. ASNHL is most likely caused by genetic and environmental interactions. The autoimmune destruction may begin in the ear itself (i.e., organ specific) or it may be a consequence of a systemic autoimmune disorder such as systemic lupus erythematosus or rheumatoid arthritis. ASNHL is most commonly treated with powerful anti-inflammatory steroids called glucocorticoids, and the treatment usually restores some hearing. Unfortunately, long-term use of these drugs is associated with significant side effects, such as susceptibility to infection, hypertension, osteoporosis, cataracts, nervousness, and insomnia. Encouraged by the success of the immunosuppressive drug methotrexate to treat rheumatoid arthritis and cancer, doctors have been substituting methotrexate for long-term treatment with glucocorticoids. NIDCD supported a large clinical study to determine whether methotrexate is effective in treating ASNHL. Unfortunately, the study showed that methotrexate was not effective in maintaining hearing recovery in individuals with ASNHL who had been previously treated with high-dose glucocorticoids. NIDCD now intends to fund research projects to better understand the mechanisms of ASNHL and develop new diagnostic tests. NIDCD hopes that this investment will translate into less toxic diagnostics and therapies that preserve natural hearing.

The Cooperative Study Group for Autoimmune Disease Prevention (CSGADP), a collaborative network of investigators who focus on halting the development of autoimmune diseases at early disease stage by means other than global immunosuppression, were renewed in FY 2012. In 2010, CSGADP supported 21 pilot projects to test approaches that may lead to the development of novel targets for disease prevention or assays for biological markers of disease progression. CSGADP is cofounded by NIDDK and the Juvenile Diabetes Research Foundation International.

In 2010, NIAID established the Human Immunology Project Consortium (HIPC) program as part of the overall NIAID focus on human immunology. Through the HIPC, centralized research resources and a comprehensive, centralized database will be constructed for use by the greater scientific community. The information gained will provide a comprehensive understanding of the human immune system and its regulation and will also serve as a foundation for the future study of immune-mediated diseases in the human, such as allergy, asthma, transplant rejection, and autoimmune diseases, and a variety of inflammatory diseases.

NIDDK plans to continue its vigorous support of research related to autoimmune diseases within its mission. For example, the over 8,000 participants being followed in TEDDY provide an unparalleled resource to study the development of the human microbiome from birth through childhood. Planned studies will build on research in mice to identify how interaction between the immune system and bacteria in the gut may alter the risk of T1D. (Other future research directions related to type 1 diabetes are found in the “Chronic Diseases and Organ Systems” section of this chapter.)

With NIDDK support, the Methotrexate Response in Treatment of Ulcerative Colitis (MERIT-UC) trial will be launched to investigate the therapeutic value of methotrexate (MTX) in adult UC patients for whom established therapies have failed.

NIDCR-supported scientists are working to validate salivary diagnostic biomarkers and to develop the related testing apparatus for Sjögren's syndrome. Sjögren’s Syndrome is also the focus of a genome-wide study to identify genetic factors that contribute to the disorder. Gene therapy is being evaluated for its potential for inserting molecules such as cytokines that could modulate inflammation in salivary glands to slow or prevent their destruction in Sjögren’s syndrome. Also, the capacity to produce molecules that enhance saliva production by residual salivary gland cells might be introduced by gene transfer. Eventually, development of artificial salivary glands may have application in patients who have lost all functional salivary glands because of radiation treatment or Sjögren’s syndrome.

282 Knox SM, et al. Science. 2010;329:1645–7. PMID: 20929848.
283 Onodera T, et al. Science. 2010;329:562–5. PMID: 20671187.
284 Trune DR, Kempton, JB. J Neuroimmunol. 2010;229(1–2):140–5. PMID: 20800906.