The immune system has always been considered the body’s protector
against disease-causing organisms and foreign bodies. The idea that a
person’s immune system could launch an attack against itself was so
unthinkable that in 1900, bacteriologist and immunologist Paul Ehrlich
coined the term horror autotoxicus to describe the body’s innate aversion to forming antibodies against itself. More than 40
years later, Mac Burnet postulated that a so-called “thymic censor”
blocked the creation of autoantibodies—antibodies that attack the self rather than foreign bodies. Burnet suggested that
these autoantibodies might be produced if the “thymic censor”
malfunctioned. We now know that autoimmunity is the failure of
the immune system to distinguish between self (the body’s
own cells, tissues, and organs) and non-self (disease-causing
organisms and other foreign substances). When this happens, the
immune system reacts as though the body is nonself and acts
accordingly—it attacks. Burnet went on to win the Nobel Prize for
subsequent work in immunology. He and Peter Medawar won the prize by
demonstrating that the body can learn to not attack a foreign
presence (e.g., a transplanted organ). This concept, called immune
tolerance, is central to many of today’s most important advances in immunology.
Introduction
Autoimmune diseases are a group of more than 80 chronic,
and often disabling, illnesses that develop when underlying
defects in the immune system lead the body to attack its own
organs, tissues, and cells. The causes of autoimmune disease
remain unknown, although genetic factors play major roles
in susceptibility. Some of these diseases may be triggered by
an infectious agent or an environmental exposure, especially in
individuals who have inherited a heightened susceptibility. Some
of the more common autoimmune diseases include rheumatoid arthritis,
type 1 diabetes, multiple sclerosis, systemic lupus erythematosus,
and inflammatory bowel disease. 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 multiple sclerosis. In contrast,
non-organ-specific diseases, such as systemic lupus erythematosus,
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.
At the same time, autoimmune diseases share some features related to
their onset and progression. In addition, overlapping genetic traits
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,
because most autoimmune diseases are more common in women than in
men, hormones are suspected of playing a role. For these and other
reasons, the autoimmune diseases are best recognized as a family of
related disorders that must be studied together as well as individually.
Most autoimmune diseases disproportionately affect women and,
as a group, are among the leading causes of death for young
and middle-aged women.38 Although treatments are available for
many 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, including
NIAID, the National Institute of Arthritis and Musculoskeletal and Skin Diseases
(NIAMS), NIDDK, NCI, NIDCR, NINDS, the National Human Genome Research Institute
(NHGRI), and NIEHS, collaborate with professional and patient advocacy organizations
to support autoimmune disease research. The Autoimmune Diseases Coordinating Committee (ADCC) facilitates inter-Institute collaboration and coordination in the development,
review, award, and post-award monitoring of solicited autoimmune diseases research programs.
Several decades of intensive research have produced a wealth
of information that has transformed conceptual understanding
of autoimmune diseases. This research has helped set the stage
for major advances in diagnosis, treatment, and prevention
interventions. However, NIH recognizes that more needs to be
done to close the gaps in knowledge and achieve the overall
goal of reducing the rising toll of autoimmune diseases.
The major tasks facing researchers in autoimmune diseases are:
- Development of a mechanism-based, conceptual understanding of autoimmune diseases
- Translation of this knowledge into new, broadly applicable strategies for treatment and prevention of multiple diseases
- Development of sensitive tools for early and definitive diagnosis, disease staging, and identification of at-risk individuals
NIH supports an array of programs to accomplish these tasks, including research and activities to:
- Advance understanding of the distribution of autoimmune diseases through epidemiological studies
- Apply the knowledge provided by the Human Genome Project toward elucidating
the hereditary risks of autoimmune diseases
- Extend understanding of genetic and environmental factors contributing to
autoimmune diseases and then develop effective prevention strategies that
arrest the autoimmune process before it can irreversibly damage the body
- Enhance the translation of scientific advances in autoimmune disease to clinical practice through the conduct of training and education activities for researchers and clinicians in collaboration with nonprofit and advocacy organizations and through effective information dissemination to patients, their families, and the public
In autoimmune diseases, a major goal of contemporary research is
to “re-educate” the immune system by using tolerance induction
strategies that aim to selectively block or prevent deleterious
immune responses while leaving protective immunity intact. Immune
tolerance will be evaluated by integrating mechanistic studies of
tolerance induction and suppression of disease into clinical research
studies and by conducting clinical trials of a variety of agents and
strategies through dedicated clinical networks.
Overarching priority areas that promise to accelerate autoimmune
disease research include biomarker development, bioinformatics,
and application of new technologies. The development of biomarkers
holds great promise for earlier and more accurate diagnosis of
autoimmune diseases, better prediction of disease flare-ups,
ceptibility genes and to study gene and protein patterns in tissue
samples. They also make it possible to characterize antibodies in serum,
which may provide vital insights into the mechanisms of onset and
progression of autoimmune disease. Bioinformatics tools, which help
scientists to assemble and analyze large amounts of data, will be
particularly important. Many of these research areas intersect with
initiatives planned under the NIH Roadmap, which fosters trans-Institute
and multidisciplinary collaboration as a way to address complex challenges
in biomedical research.
Burden of Illness and Related Health Statistics
Although many individual autoimmune diseases are rare, collectively
they affect millions of Americans, and for unknown reasons, their
prevalence is rising. Examples of prevalence and incidence
statistics for some autoimmune diseases are:
- An estimated 2.1 million people in the United States (about 1 percent of the population),
including about 30,000 to 50,000 children, have rheumatoid arthritis.39
- About 730,000 to 1.5 million people have type 1 diabetes (National Diabetes Fact Sheet, 2005).
About 15,000 people younger than age 20 are diagnosed annually with type 1 diabetes.40
- An estimated 250,000 to 350,000 people in the United States have been diagnosed with multiple sclerosis.41
- In the United States, 239,000 people have been diagnosed with or are suspected to have systemic lupus erythematosus.42
- As many as 1.4 million people in the United States have inflammatory bowel disease.43
For more information, see http://www3.niaid.nih.gov/topics/autoimmune/PDF/ADCCFinal.pdf
NIH Funding for Autoimmune Disease Research
In FYs 2006 and 2007, NIH funding for autoimmune diseases research was $598 million
and $587 million respectively. The table at the end of this chapter indicates some
of the research areas supported by this investment (see “Estimates of Funding for
Various Diseases, Conditions, and Research Areas”).
Summary of NIH Activities
NIH seeks to understand the onset and progression of autoimmune diseases and to use that knowledge to develop better interventions for disease
prevention, diagnosis, and treatment. With more than 80 distinct autoimmune diseases, this may seem to be a daunting task. However, the many
commonalities in the mechanisms that cause autoimmune disorders means that research on one autoimmune disease often advances our understanding
of others.
Providing Research Resources and Infrastructure
Disease Registries
Many autoimmune diseases are rare, and researchers often must engage in national and international collaborativ
research to ensure access to sufficient numbers of patients and tissue samples to conduct their studies. NIH
provides resources to facilitate these research efforts. For example, disease registries provide an important
epidemiological resource for tracing the natural history of autoimmune diseases, assessing its burden in different
populations, and identifying and tracking trends in incidence and prevalence. NIH supports patient registries for
numerous autoimmune diseases, including alopecia areata, ankylosing spondylitis, antiphospholipid syndrome,
epidermolysis bullosa acquisita, juvenile and adult-onset rheumatoid arthritis, lupus, neonatal lupus, and
scleroderma. Some of these registries also contain relevant clinical data linked to tissue samples.
Other Research Resources
NIH-supported research resources also include programs for the preclinical development of therapeutic
agents, such as the Type 1 Diabetes-Rapid Access to Intervention Development Program; biological
specimen repositories; animal models; provision of genetic, genomic, and other molecular assays for
specific projects; clinical trials infrastructure; and assistance in identifying collaborators. Some
of these resources are mentioned in more detail in the “Notable Examples” later in this section.
Identifying Environmental Triggers of Autoimmune Diseases
Two large-scale projects that are searching for environmental triggers
of autoimmune diseases are the Carolina Lupus Study and The Environmental Determinants of Diabetes in the Young (TEDDY) study. The Carolina Lupus
Study, initiated in 1997, was the first population-based epidemiological
study to examine the influence of hormonal and occupational exposures on lupus.
The investigators found a striking association between occupational exposure
to silica dust and lupus in individuals living in North and South Carolina.
They also found that, compared with people who did not have lupus, patients
with lupus were more likely to self-report occupational exposure to mercury,
agricultural work that involved mixing pesticides, or work in a dental office
or laboratory.44 These and similar findings are expected to lead to improved
prevention strategies for lupus and other autoimmune diseases and suggest
possibilities for studies of the molecular development of lupus.
TEDDY is pinpointing environmental factors–such as infectious agents or
diet–that can trigger type 1 diabetes in genetically susceptible individuals.
This international consortium is following individuals who are at high genetic
risk for type 1 diabetes from birth until age 15 to discover how environmental
factors after birth contribute to the development of prediabetic autoimmunity
and type 1 diabetes. Because type 1 diabetes and celiac disease share similar
genetic predispositions, TEDDY investigators also are examining environmental
triggers of celiac disease. The dataset and biologic samples amassed in
TEDDY will provide a valuable resource for future studies.
Understanding the Genetics of Autoimmune Diseases
NIH-supported scientists are identifying the genetic underpinnings of autoimmune disorders,
research that can elucidate molecular pathways of disease and possible therapeutic targets.
For example, investigators recently showed that a gene called PSORS1 plays a role in determining
who gets psoriasis. Individuals with a particular form of this gene (the HLA-Cw6 allele) are more
likely to develop early-onset psoriasis.45 Scientists hope that further research will lead to a
treatment that interferes with the disease by targeting the PSORS1 gene. Researchers
also have discovered genes that variously appear to play roles in lupus,
rheumatoid arthritis, inflammatory bowel disease, and alopecia areata, bringing us
a step closer to understanding the mechanisms of these diseases.46
Recent technological advances have led to the development of
genome-wide association studies that compare the genomes of
people with an illness to those of people without the illness.
Through this comparison, it becomes possible to identify even
subtle genetic differences between affected and unaffected people
(see the Genomics section in Chapter 3 for more information
about genome-wide association studies). Genome-wide analysis is
beginning to yield important results in the study of autoimmune
diseases. For example, recent studies have led to the identification
of key genes involved in type 1 diabetes47 and inflammatory bowel disease.48 Recent technological advances have led to the development of genome-wide association
studies that compare the genomes of people with an illness to those of people
without the illness. Through this comparison, it becomes possible to identify
even subtle genetic differences between affected and unaffected people
(see the Genomics section for more information about genome-wide association studies).
Genome-wide analysis is beginning to yield important results in the study of autoimmune
diseases, including the identification of key genes involved in type 1 diabetes
and IBD. In other research, investigators using a large familial dataset found the first
new genes linked to MS in more than 20 years. These genes code for proteins that
influence the way T cells patrol the body for pathogens, shedding light on a
possible mechanism of MS onset and progression.49 In a similar quest to identify disease genes, the Type 1 Diabetes Genetics Consortium is studying families with two or more siblings with type 1 diabetes.
In addition, NIH supports the Genetic Association Information Network (GAIN), which provides genotyping services, including genome-wide association
studies to enhance and extend the utility of existing of research efforts.
Through GAIN, NIH supports a long-term collaboration in which investigators
are seeking to identify new genetic susceptibility factors for the development of psoriasis.”
Understanding the Mechanisms of Autoimmune Disease Onset and Progression
NIH sponsors research to illuminate the causes of autoimmune diseases
and the regulatory mechanisms that control autoantibody production and
function. For example, researchers recently used a mouse model to show
that toll-like receptors, a set of immune receptors involved in the
earliest immune responses to infection and long thought to play a key
role in autoimmune responses, are indeed implicated. They showed that
even minor mutations in toll-like receptors can spark autoimmunity,
suggesting that this family of proteins could be an important therapeutic
target for lupus or other autoimmune diseases.50 Related research showed
that a recently identified joint protein, cadherin 11, plays a role in
rheumatoid arthritis in a mouse model of the disease. The investigators
showed that a treatment that targets this protein prevents the abnormal
adhesion and cartilage destruction typical of rheumatoid arthritis
in mice, revealing a potential new therapeutic target in humans.51
NIH supports a range of initiatives such as the following to better
understand the mechanisms of autoimmune disease onset and progression
and to develop effective interventions.
The Cooperative Study Group for Autoimmune Disease Prevention, established
in 2001, is a collaborative network of investigators devoted to understanding
the functioning of the immune system in both health and autoimmune disease.
The Study Group works to develop the knowledge base necessary to design safe
and effective interventions for the prevention of autoimmune disorders.
Participating centers support preclinical research, innovative pilot
projects, and noninterventional clinical studies, with an emphasis
on type 1 diabetes. The Study Group, renewed recently for another
5 years, includes six cooperative agreements among researchers across the Nation.
The Beta Cell Biology Consortium (BCBC) is a team science initiative
established in 2001 and competitively continued in 2005. This program
facilitates interdisciplinary approaches to advance the understanding
of insulin-producing pancreatic beta cell development and function.
Currently, BCBC consists of 29 scientists, the majority of whom
participate as investigators on 10 cooperative agreements.
Scientists from two intramural NIH laboratories also are involved.
In addition to conducting research, the Consortium develops research
resources, such as antibodies, mouse models, and gene arrays,
for use by the scientific community.
Scientists studying autoimmune diseases are excited about the emerging
research approach known as systems biology that seeks to understand the
overall behavior of biological systems. Systems biology uses computational
methods to analyze data or simulate the system of interest and requires
collaboration among researchers from bioinformatics, computer science,
molecular biology, genomics, and other disciplines. NIH-supported researchers
are applying a systems biology approach to better understand SjÓgren’s syndrome,
an autoimmune disorder in which immune cells attack and destroy the glands that
produce tears and saliva, and other salivary gland disorders. Salivary gland
biology is conducive to systems biology because researchers already
have extensively catalogued the genes and proteins expressed in
salivary glands. The scientific opportunity is to create an integrative,
quantitative, and dynamic model encompassing every known aspect of the
molecular and cellular biology of salivary glands and to translate this
model into precise and practical ways to treat SjÔgren’s syndrome.
Improving the Diagnosis and Prognosis of Autoimmune Diseases
Biomarker research is one area of investigation that may lead to
better techniques for diagnosing autoimmune disorders. Biomarkers,
clinical signs that correlate with the onset or progression of
disease, already are commonly used to help diagnose some diseases,
including prostate cancer and certain types of heart disease.
With the rise of technologies to identify and test biomarkers
more quickly, this area of research holds great promise for earlier
and more accurate autoimmune disease diagnosis, better prediction of
disease flare-ups, and improved monitoring of disease progression
and response to treatment.
Recent progress in identifying biomarkers for lupus provides an
example of NIH’s work in this area. For example, researchers have
identified biomarkers that can be detected in the urine of patients
with kidney disease and that provide information about the type and
severity of disease.52 If validated with further research, these
biomarkers may provide the basis for a noninvasive test to replace
repeated kidney biopsies in patients with lupus, who are at increased
risk for potentially severe kidney disease.
The Biomarkers Consortium,
of which NIH is a founding partner,
recently approved the concept for a systemic lupus erythematosus
Biomarkers Working Group. The Consortium is a public-private partnership
that endeavors to discover, develop, and qualify biomarkers to identify
risk for disease, make a diagnosis, and guide treatment. The systemic
lupus erythematosus Biomarkers Working Group will focus on identifying
and validating biomarkers for prognosis and assessment of lupus disease
activity, with the goal of speeding drug discovery and evaluation of
new therapies in a disease that has not had a new drug approved in 40 years.
This work also may lead to the identification of common biomarkers
for other autoimmune diseases.
Developing Evidence-Based Treatment and Prevention Interventions
NIH supports the development of effective clinical strategies to prevent
and treat autoimmune diseases and the translation of successful
strategies to clinical application. The following programs and
initiatives highlight NIH’s work in this area.
The Autoimmunity Centers of Excellence (ACEs) encourage and enable
collaborative research–across scientific disciplines and medical
specialties, and between basic and clinical scientists–to test prevention
and treatment interventions. Nine ACEs focus on strategies that induce
immune tolerance or regulate the immune system. Researchers also explore
the molecular mechanisms underlying the agents evaluated in ACE trials.
The enhanced interactions between basic and clinical researchers help
to accelerate the translation of research findings into medical applications.
ACE currently is supporting 10 active clinical trials studying treatments
for lupus, multiple sclerosis, pemphigus vulgaris, rheumatoid arthritis,
and SjÔgren’s syndrome.
The Clinical Islet Transplantation Consortium develops and implements
a program of single- and multicenter clinical studies, with accompanying
mechanistic studies, in islet transplantation for the treatment of type 1
diabetes. The Consortium is focused on improving the safety and long-term
success of methods for transplanting islets, the insulin-producing cells
of the pancreas, in people whose own islets have been destroyed by the
autoimmune process that characterizes type 1 diabetes. Some studies will
focus on improving combined islet and kidney transplants in patients with
type 1 diabetes who have kidney failure, a common diabetes complication.
The Immune Tolerance Network (ITN) is a collaborative research effort to
study and test new drugs and therapies for autoimmune diseases and other
immune-related disorders. ITN studies are based on stimulating immunological
tolerance, the mechanism by which the immune system naturally avoids damage to self.
Today, autoimmune diseases are commonly managed with immunosuppressive agents.
Because these agents broadly reduce the immune response, they place patients
at increased risk for infection. The ITN supports four clinical studies with
the goal of identifying and developing interventions that selectively target
harmful autoimmune responses, avoiding the burdensome and dangerous side
effects of global immunosuppression. For example, researchers are evaluating
agents that suppress the activity of proteins known to be involved in the
pathology of many autoimmune diseases. These proteins include the major
histocompatibility complex, large protein clusters that are heavily involved
in immune function; T cell receptors, which help lymphocytes (a type of immune cell)
recognize foreign material; and autoantigens, normal proteins or other molecules
that are mistakenly recognized by the immune system.
The development of therapeutic vaccines is a promising approach being
taken by ITN scientists. One therapeutic vaccine in development, called
the “universal” major histocompatibility complex (MHC) class II peptide
vaccine, might be used to treat a wide variety of autoimmune disorders.
The vaccine’s target peptide–a short portion of a protein–is present in
many of the molecules known to be associated with the pathology of
rheumatoid arthritis. Because of this “universality,” one vaccine can be
used to simultaneously disrupt multiple molecular pathways of rheumatoid
arthritis, increasing the likelihood of treatment success.
One clinical trial of special note is the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial. The SCOT trial will compare the potential
benefits of stem cell transplant and high-dose monthly cyclophosphamide
(Cytoxan) in the treatment of scleroderma. This approach differs from
current organ-specific treatments by seeking to treat the immune system as a whole.
Addressing the Comorbidities of Autoimmune Diseases
Another strategy for reducing the burden of disease is to support
research to understand, prevent, diagnose, and treat comorbidities
that affect many patients with autoimmune diseases. Comorbidities
range from the presence of more than one autoimmune disease to
conditions arising from immune attack on various body tissues or
the interventions necessary to treat autoimmune disease. For example,
a study of families with vitiligo, a pigmentation disorder in which
white patches of skin appear on different parts of the body, found
that family members of patients with vitiligo are predisposed to
other, potentially more serious, autoimmune diseases. 53 This finding
may increase the ability to diagnose autoimmune diseases earlier,
which could lead to better treatment.
Patients with type 1 diabetes are at increased risk for eye disorders,
nerve and kidney damage, and heart disease. The landmark Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study has shown that intensive control of blood glucose levels reduces the development of
these long-term and often life-threatening diabetes complications.54 In other research,
investigators have identified potential molecular targets for prevention
or treatment of chronic periodontitis, which can be a complication of diabetes.55
Notable Examples of NIH Activity
Key for Bulleted Items:
|
E = Supported through Extramural research
I = Supported through Intramural research
O = Other (e.g., policy, planning, or communication)
COE = Supported through a congressionally mandated Center of Excellence program
GPRA Goal = Concerns progress tracked under the Government Performance and Results Act
|
|
Providing Research Resource and Infrastructure
Type 1 Diabetes–Rapid Access to Intervention Development (T1D-RAID): Many
investigators who have discovered promising therapeutic agents in the
laboratory do not have the resources to ready the agents for use in human
clinical trials. Therefore, NIH supports the T1D-RAID program to provide
resources for preclinical development of agents to test in clinical trials.
For example, the drug lisofylline, which was prepared and tested under the
T1D-RAID program, will be studied in an upcoming pancreatic islet transplantation
clinical trial.
Identifying Environmental Triggers of Autoimmune Diseases
Carolina Lupus Study: Since 1997, NIH has supported the Carolina Lupus
Study, the first population-based epidemiological study to examine the
influence of hormonal and occupational exposures, as well as the genetic
factors that affect immune function and metabolism, on systemic lupus
erythematosus. Lupus is a severe, disabling autoimmune disease that can
lead to morbidity and mortality from renal and cardiovascular disease.
African Americans are two to three times more likely than Whites to
develop the disease, for unknown reasons. The study included 265 patients
and 355 people without lupus living in 60 counties in North and South
Carolina. The results of analysis of occupational exposure to silica dust
in relation to risk for systemic lupus erythematosus were striking.
Other associations were seen with self-reported occupational exposure to
mercury, in mixing pesticides for agricultural work, and among dental
workers. Weaker associations were seen between systemic lupus erythematosus
and shift work and among health care workers with patient contact.
Understanding the Genetics of Autoimmune Diseases
Multiple Sclerosis: While the exact cause of multiple sclerosis is unknown,
research suggests a strong genetic component. NIH funds a number of studies
to determine the underlying genetic causes of multiple sclerosis, including
a project to identify regions of the genome containing multiple sclerosis
susceptibility genes by using a large familial dataset and genomic analysis
tools. NIH also funds clinical trials to test therapies for multiple sclerosis,
including the CombiRx trial, a randomized, controlled clinical trial comparing
the efficacy of treatment combining interferon-beta and glatiramer acetate
versus treatment with a single agent for relapsing forms of multiple sclerosis.
A study conducted in conjunction with CombiRx by NIH intramural researchers
(BioMS) is assessing multiple sclerosis biomarkers by using genomic and
proteomic technology and relating the information obtained back to clinical
and MRI data generated by the CombiRx clinical trial.
Autoimmune Diseases and Genetics: With the advancement of genomic science, more information has been gained about the genetic component of autoimmune diseases. Susceptibility genes have been identified for rheumatoid arthritis, lupus, psoriasis, and alopecia areata. Understanding the genetic influence of these diseases provides essential information for the design of new therapies.
- Kumar KR, et al. Science 2006;312:1665-9, PMID: 16778059
- Nair RP, et al. Am J Hum Genet 78:827-51, PMID: 16642438
- Haas CS, et al. Arthritis Rheum 2006;54:2047-60, PMID: 16804865
- Martinez-Mir A, et al. Am J Hum Genet 2007;80:316-28, PMID: 17236136
- Remmers EF, et al. N Engl J Med 2007 Sep 6;357:977-86, PMID: 17804842
- For more information, see
http://www.niams.nih.gov/News_and_Events/Spotlight_on_Research/2006/lupus_susceptibility_gene.asp
- For more information, see
http://www.niams.nih.gov/News_and_Events/Spotlight_on_Research/2006/psoriasis_gene.asp
- For more information, see
http://www.niams.nih.gov/News_and_Events/Spotlight_on_Research/2006/three_genes_ra.asp
- For more information, see
http://www.niams.nih.gov/News_and_Events/Spotlight_on_Research/2007/alopecia_areata.asp
- For more information, see
http://www.niams.nih.gov/News_and_Events/Press_Releases/2007/09_06.asp
- This example also appears in Chapter 3: Disease Registries, Databases, and Biomedical Information Systems.
- (E) (NIAMS, NCRR, NHLBI, NIAID, NIMH)
Genetic Susceptibility for Alopecia Areata: Scientists supported by NIH have identified loci on four chromosomes that appear to play a role in the development of alopecia areata, an autoimmune disease characterized by hair loss that can affect the whole scalp or, in rarer cases, the entire body. Many U.S. families recruited for the study were identified through the Alopecia Areata Registry.
Understanding the Mechanisms of Autoimmune Disease Onset and Progression
The Cooperative Study Group for Autoimmune Disease Prevention: In 2006,
NIH renewed the Cooperative Study Group for Autoimmune Disease Prevention,
which was established in 2001. This collaborative network is devoted to
understanding immune homeostasis in both health and autoimmune diseases
and to developing interventions to prevent autoimmune disease. The six
participating Centers support preclinical research, innovative pilot
projects, and noninterventional clinical studies, with an emphasis
on type 1 diabetes. By the end of 2006, grantees had published 109
original research papers, and 5 of 48 pilot projects had matured into
investigator-initiated grants. Of note, the Centers are collaborating on
the “Roadmap to Inflammation in the NOD [non-obese diabetic] Mouse”
project, which will identify and characterize genes and proteins involved in
the development of diabetes and study the mechanisms by which diabetes develops.
Systems Biology Approach to Salivary Gland Physiology: Previous
research has catalogued the genes and proteins expressed in the salivary glands.
This initiative puts those catalogues into context by defining when and where
genes and proteins are expressed and how they function as parts of a fully
integrated biological system. The initiative combines the power of mathematics,
biology, genomics, computer science, and other disciplines to translate
this highly detailed information into more precise and practical leads to
treat SjÔgren’s syndrome, a debilitating autoimmune disorder that affects
millions of Americans. The initiative also will help in learning to use saliva
as a diagnostic fluid for a variety of conditions, from AIDS to cancer to diabetes.
Beta Cell Biology Consortium (BCBC): The BCBC is collaboratively
pursuing key challenges relevant to the development of therapies for type 1
and type 2 diabetes, including studying pancreatic development to understand
how insulin-producing beta cells are made, exploring the potential of stem
cells as a source for making islets, and determining the mechanisms underlying
beta cell regeneration. The BCBC has generated key research resources, such
as animal models, microarrays, and antibodies, which are available to the scientific community.
- For more information, see http://www.betacell.org
- This example also appears in Chapter 2: Chronic Diseases and Organ Systems and Chapter 3: Molecular Biology and Basic Sciences
- (E) (NIDDK)
Promising New Route to Rheumatoid Arthritis Therapy: Rheumatoid
arthritis is a debilitating autoimmune disease that is characterized by
joint inflammation and affects approximately 2.1 million Americans. In this
disease, a thin membrane of the joint, the synovium, overgrows and attaches
abnormally to cartilage, leading to its erosion. A recently identified joint
protein, cadherin 11, mediates the disease in a mouse model. Blocking synovium
attachment to cadherin 11 prevents this abnormal adhesion and cartilage
destruction in mice and reveals a potential new therapeutic target for the disease in humans.
New Molecular Targets to Halt Periodontal Bone Loss: Approximately
80 percent of American adults have some form of periodontal disease.
Chronic periodontitis erodes supporting structures of the tooth, leading
to tooth loss. The risk of periodontal diseases is higher in smokers and
individuals with diabetes; 18 million Americans suffer from diabetes and
related complications, including increased incidence and severity of periodontitis.
This higher incidence and severity are associated with increased cell death in bone-
and tissue-forming cells called osteoblasts and fibroblasts. The loss of these cells
results in decreased capacity to repair tissue and bone. NIH-supported investigators
published two separate papers describing the mechanisms by which the diabetic state
enhances cell death. The papers suggest that diabetes-induced cell death and compromised
tissue repair are mediated by the TNF-a pro-apoptotic pathway, and the major effector
is caspase-3. Inhibition of TNF-a or caspase-3 activity reduces cell death and
restores repair capacity. Discrimination between harmful microbes and commensal
species is a critical property of the mucosal immune system, which is essential for
maintaining health. Host immune cells have surface receptors that recognize bacterial
species such as those known to be associated with periodontitis. Host immune cells
can selectively learn to respond strongly or to tolerate endotoxin produced by
recognized bacteria. NIH-supported scientists found that patients with chronic
periodontitis overproduce a molecule known as SHIP, which plays an important
regulatory role in signaling immune cells to tolerate endotoxin. The data from
these studies suggest possible targets for developing new ways to treat or
prevent chronic periodontitis.
Trans-NIH Initiative for Translational Research in Immunology, Autoimmunity,
and Inflammation: A new, trans-NIH initiative is being developed by the
intramural research program to facilitate the translation of advances in basic
immunology to improved therapies and clinical care for immune-mediated diseases.
The translation of basic immunology to the clinic has been impeded by separations
between basic immunologists, physicians, and epidemiologists and by barriers among
clinicians who address diseases that share pathophysiologic mechanisms but are
historically separated in different specialty practices. The new program will
integrate research efforts not only across the basic, clinical, and population
sciences but also across conventional medical subspecialties. Research will focus
on a variety of autoimmune diseases, congenital and acquired immunodeficiency syndromes,
processes in which inflammation or altered immunity has a pathogenic role, and
malignant diseases influenced by the immune system. Studies will address the
underlying role of the immune system and the similarities and differences of
the inflammatory response in many seemingly unrelated immune-mediated diseases.
The initiative is expected to advance understanding of the causes of the diseases
and to promote the development of new therapies. It also is expected to serve as
a model for future trans-NIH translational research efforts to facilitate more rapid
development and testing of new therapies and enhance interdisciplinary training.
- This example also appears in Chapter 3: Clinical and Translational Research.
- (I) (NHLBI, NIAID, NIAMS, NIDDK)
Improving the Diagnosis and Prognosis of Autoimmune Diseases
Monitoring Organ Rejection Using MRI: Organ transplants give patients
a new lease on life. However, preventing the immune systems from rejecting
the transplanted organ sometimes presents a challenge. Physicians must strike
a balance between suppressing the immune system so that it does not reject the
organ and maintaining enough immune activity to ward off infections. Tracking
how the body accepts the new organ is critical to this process. The
current “gold standard” for monitoring organ rejection is tissue biopsy,
an invasive procedure in which a physician removes a small sample of the
transplanted organ for testing. Biopsy has two drawbacks: patient discomfort
(the physician must perform the procedure multiple times) and poor selectivity
(biopsy removes tissue from only a limited number of sites and can miss rejection
starting elsewhere in the organ). To overcome these limitations, NIH-supported
researchers are developing a new method to monitor organ rejection with MRI.
They label macrophages (immune cells) with polymer-coated, micron-sized iron
oxide particles. These magnetic particles allow the migration of the macrophages
to rejection sites in the transplanted organ to be clearly tracked by MRI. At present,
this work is being performed on rats, but the investigators are extending it to
large animals and humans. If successful, the approach could be used to optimize
the administration of immunosuppressant drugs in clinical situations.
Developing Evidence-Based Treatment and Prevention Intervention
The Immune Tolerance Network: In 2007, NIH renewed support
for the Immune Tolerance Network (ITN), a consortium of more than 80
investigators in the United States, Canada, Europe, and Australia.
The ITN studies and tests new drugs and therapies for autoimmune
diseases, asthma and allergies, and rejection of transplanted organs,
tissues, and cells. ITN studies are based on stimulating immunological
tolerance, the mechanism by which the immune system naturally avoids
damage to self. Immune tolerance approaches aim to “re-educate” the
immune system to eliminate harmful immune responses and graft rejection
while preserving protective immunity against infectious agents. The
ITN has established state-of-the art core laboratory facilities to
study the underlying mechanisms of candidate therapies and to monitor
tolerance. In 2006, the ITN reported that a novel DNA-based ragweed
allergy therapy could achieve long-lasting symptom reduction after
only 6 weeks of therapy, compared with current methods that require
years of biweekly injections. Current ITN studies include pancreatic
islet transplantation for type 1 diabetes, approaches to slow or
reverse the progression of autoimmune diseases, approaches to treat
and prevent asthma and allergic disorders such as food allergy, and
therapies to prevent liver and kidney transplant rejection without
causing harmful suppression of immunity.
Addressing the Comorbidities of Autoimmune Diseases
Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions
and Complications (EDIC): The DCCT demonstrated that intensive control of blood
glucose levels reduced complications of the eyes, nerves, and kidneys in type 1
diabetes patients. Long-term findings from the follow-on EDIC study show that
intensive control lowers risk of heart disease. This research revolutionized
disease management, leading to the recommendation that patients should begin
intensive therapy as early as possible. EDIC recently found that recurrent
hypoglycemia associated with intensive control does not affect patients’
long-term cognitive function. After more than 20 years of studying this
patient cohort, crucial insights continue to emerge.
Comorbidities: Many autoimmune diseases affect multiple
organ systems. Recent studies have identified the basis of concurrent
diseases at a molecular level, as well as clinically. A biomarker for
lupus-related kidney disease has led to a noninvasive diagnostic
breakthrough. Patients with the skin pigmentation disease vitiligo
are at increased risk for other autoimmune diseases. In addition,
recent studies document an increased risk for cardiovascular disease
among patients with rheumatoid arthritis.
- Laberge G, et al. Pigment Cell Res 2005;18:300-5, PMID: 16029422
- Giles GT, et al. Arthritis Res Ther 2005;7:195-207, PMID: 16207349
- Varghese SA, et al. J Am Soc Nephrol 2007;18:913-22, PMID: 17301191
- For more information, see http://www.niams.nih.gov/News_and_Events/Spotlight_on_Research/2006/lupus_kidney.asp
- For more information, see http://www.niams.nih.gov/News_and_Events/Spotlight_on_Research/2006/vitiligo_risk.asp
- For more information, see http://www.niams.nih.gov/News_and_Events/Spotlight_on_Research/2006/journal_special_text.asp
- (E) (NIAMS, NCRR, NHLBI, NIAID)
Vitiligo: Vitiligo is a skin disease characterized by a loss of
pigment in all people who are affected. The psychological and social
consequences can be particularly profound in affected people of color.
A study of 133 families with vitiligo found that family members–even
those who do not have vitiligo–are also predisposed to other, potentially
more serious autoimmune diseases.
NIH Strategic Plans Pertaining to Autoimmune Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
National Institute of Dental and Craniofacial Research (NIDCR)
National Institute of Allergy and Infectious Diseases (NIAID)
National Center for Complementary and Alternative Medicine (NCCAM)
Trans-NIH Plans
- NIH Autoimmune Diseases Coordinating Committee: Autoimmune Diseases Research Plan
CSR, FIC, NCCAM, NCI, NCRR, NEI, NHGRI, NHLBI, NIA, NIAAA, NIAID, NIAMS, NIBIB, NICHD, NIDA, NIDCD, NIDCR, NIDDK, NIEHS, NIGMS, NIMH, NINDS, NINR, ORD, ORWH
- NIH Action Plan for Transplantation Research (2007)
NCI, NHLBI, NIA, NIAAA, NIAID, NIAMS, NIBIB, NIDA, NIDCR, NIDDK, NIMH, NINDS
- Advances and Emerging Opportunities in Type 1 Diabetes Research: A Strategic Plan
CC, CSR, NCCAM , NCMHD, NCRR, NEI, NHGRI, NHLBI, NIA, NIAAA, NIAID, NIBIB, NICHD, NIDA, NIDCD, NIDCR, NIDDK, NIEHS, NIGMS, NIMH, NINDS, NINR, NLM
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