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Report on the Rare Diseases and Conditions Research Activities of the National Institutes of Health 1999

National Institute of Allergy and Infectious Diseases (NIAID)

Overview of Rare Diseases Research Activites

NIAID supports research related to many diseases that are classified as rare. This research falls primarily in three areas: infectious diseases, autoimmune diseases, and primary immunodeficiency diseases.

Rare infectious diseases include acute and chronic conditions caused by parasites, bacteria, viruses, and fungi. Several rare infectious diseases are classified as "emerging" or "reemerging"; these have the potential to cause outbreaks at the regional level. Lyme disease, cryptosporidiosis, hantavirus pulmonary syndrome, and coccidioidomycosis are included in these categories. Some diseases, including poliomyelitis, pertussis, diptheria, and measles, have become rare because of preventive childhood vaccinations. Another group of infectious diseases of special interest to the NIAID is the "opportunistic infections" that frequently affect people with compromised immune systems, especially individuals infected with the human immunodeficiency virus (HIV). Toxoplasmosis, cryptosporidiosis, pneumocystis pneumonia, cytomegalovirus retinitis, and Kaposi's sarcoma are examples of rare opportunistic infections. Research on rare infectious diseases is aimed at delineating mechanisms of disease pathogenesis and developing more effective diagnosis, prevention, and treatment strategies.

Autoimmune diseases are characterized by immune responses against the body's own tissue. Whereas the underlying cause of many autoimmune diseases remains unknown, genetic, environmental, and immunological factors are thought to be involved. Rare autoimmune diseases include scleroderma (a disease of the skin), myasthenia gravis (a disease affecting muscle function), and the various types of vasculitis (diseases that attack blood vessels in various organs). NIAID research on autoimmune diseases is focused on identifying the pathogenesis of these diseases and developing new approaches to prevention and treatment.

Primary immunodeficiency diseases are hereditary disorders characterized by an unusual susceptibility to infection resulting from diminished immune system function. These diseases, affecting approximately 500,000 individuals in the United States, range in severity from relatively mild to fatal. NIAID research in this area is geared toward identifying the defective genes (which has already been accomplished for some diseases), defining the physiological roles of these genes, and, ultimately, developing approaches to correct these defects.

Recent Scientific Advances in Rare Diseases Research

Rare Infectious Diseases

Ehrlichiosis. Human ehrlichiosis is a rapidly emerging tick-borne infection known to be caused by Ehrlichia chaffeensis, E. sennetsu, E. canis, or the agent of human granulocytic ehrlichiosis (HGE), which is closely related, if not identical, to E. phagocytophila and E. equi. It is an acute disease that causes headache and fever. Scientists recently identified a new species of Ehrlichia that causes ehrlichiosis. They conducted an extensive serological study with specimens collected from 413 patients with possible ehrlichiosis and found that infection with E. ewingii results in a disease that is clinically indistinguishable from infection caused by E. chaffeensis or the agent of HGE.

During FY 1999, scientists determined that the ability of the HGE agent to infect neutrophils but not other cells is based on the presence of the cell surface marker CD15. Monoclonal antibodies against CD15 block the HGE agent from infecting-but not from adhering to-target cells; they also inhibit intracellular growth of the HGE agent. Because mutant cell lines deficient in CD15 are resistant to infection by the HGE agent, CD15 appears to play a major role in the pathogenesis of this infection.

Giardiasis. Infection with the protozoan parasite Giardia lamblia may cause diarrhea, dyspepsia, and, occasionally, malabsorption. G. lamblia is a member of one of the earliest diverging eukaryotic lineages and, as such, has retained properties of both prokaryotes and eukaryotes. Sequence analysis of the Giardia genome is important because it may yield important data regarding the evolution of prokaryote/eukaryote cellular functions and because Giardia is an important human pathogen. Investigators have analyzed about 9% of the Giardia genome, sufficient to confirm the hypothesis that the organism is a "mosaic" of eukaryotic and prokaryotic divergence. Sequencing of the full genome of this small organism is the next step in this project.

Hepatitis D. Hepatitis D virus (HDV) is a coinfection with hepatitis B, which may lead to a more serious, rapid-onset liver disease. To date, no specific therapy exists for HDV. The viral RNA consists of two major antigens-large and small -antigens. A specific site on the large -antigen, known as a prenylation site, is critical to complete particle assembly. In a tissue culture model, researchers have shown that inhibition of the prenylation site with the cancer drug BZA-5B abolishes HDV particle production. A possible question for investigation is whether BZA-5B will be therapeutic in patients with hepatitis D.

Hepatitis SEN/V. The members of the hepatitis family of viruses cause inflammation of the liver. During FY 1999, a new contender was added to the expansive alphabet of hepatitis A, B, C, D, E, (F), and G viruses. SEN/V was discovered by an Italian investigator in an immunosuppressed HIV+ patient with hepatitis. Further investigations of other patients with non-A-E hepatitis has revealed a high incidence of the new strain.

Lyme Disease. Lyme borreliosis is a tick-borne bacterial disease that causes a wide range of clinical symptoms, including skin lesions, arthritis, and, rarely, chronic neurological symptoms. When an infected nymphal tick feeds on a host, the bacteria multiply within the tick. They then invade the tick's salivary glands, through which they can be transmitted to a mammalian host to initiate infection. During FY 1999, NIAID-supported scientists made several advances in understanding Borrelia burgdorferi and the diseases it causes. Scientists found that the degree of genetic diversity observed for cultured clinical isolates of B. burgdorferi depends on the particular experimental approach.

The DNA sequence of the plasmid component of the B. burgdorferi genome has been completed. This segment of the genome is a unique feature of the spirochete and is predicted to be important in the infectious cycle. Intramural NIAID scientists have developed molecular genetic methods for B. burgdorferi and have begun to apply them to test the function of particular genes implicated in the transmission or chronic persistence of spirochetes in ticks or mammals. These scientists, in collaboration with the CDC, also demonstrated that the Lyme disease spirochete rapidly switches its outer surface proteins (from OspA to OspC) associated with the transmission of these bacteria during a tick bite.

On December 21, 1998, the U.S. Food and Drug Administration (FDA) licensed LYMErix (SmithKline Beecham Biologicals), a new vaccine against Lyme disease that stimulates the production of antibodies against the OspA surface protein of B. burgdorferi. This vaccine is designed to prevent the transmission of disease by infected ticks. After three injections, it is judged to be 80% effective in preventing borreliosis in humans between 15 and 70 years of age. Also during FY 1999, other scientists found that antibodies against OspA interfere with the ability of B. burgdorferi to invade the salivary glands of infected ticks, thereby blocking the transmission of infection. Additionally, researchers analyzed the results of phase III trials, which indicate that vaccine efficacy is directly related to the titer of anti-OspA antibody generated and the ability of such an antibody to kill spirochetes within the midgut of infected ticks. Because complement is known to be inactivated by components of tick saliva, the ability of anti-OspA antibody elicited in immunized monkeys to kill B. burgdorferi in vitro, in both the presence and absence of complement, was investigated. Depending on the strains of B. burgdorferi used, killing in the absence of complement was between 14 and 3,800 times less efficient; thus, the relative inefficiency of killing by anti-OspA antibody in the absence of complement may account for the fact that OspA vaccine efficacy is critically dependent on antibody titer.

Nontypeable Haemophilus influenzae. Nontypeable Haemophilus influenzae (NtHi) is one of the most common causes of respiratory tract infections in chronic obstructive pulmonary disease, which includes chronic bronchitis and emphysema. Studies have shown that NtHi lipooligosaccharide (LOS) may aid in the attachment of NtHi to airway epithelial cell surfaces. Scientists pinpointed a sugar residue on LOS that is essential for binding to airway surfaces. This knowledge may lead to a way to block binding of NtHi.

Pertussis. Bordetella pertussis is the primary etiological agent of pertussis (whooping cough). Pertussis was widespread before the development of immunization and had high morbidity and mortality rates in infants and young children. Scientists working at several locations are evaluating the protective efficacy, safety, and immunogenicity of a three-component acellular pertussis vaccine produced by SmithKline Beecham in healthy adolescents and adults. The trial ended in December 1999, and analysis of the results continues.

To learn more about the organism and understand what responses it elicits when it infects, investigators are using high-density cDNA microarrays to analyze the responses of 16,000 human genes (about 20% of all expressed human genes) to B. pertussis and B. bronchiseptica and to mutant strains, each with defects in different virulence factors. Scientists observed that each bacterial species and each of the well-known Bordetella toxins appear to induce a characteristic set of responses in human cells, which can be used to both identify and better understand the manner by which the human host recognizes a disease-causing bacterium. The detection of characteristic response signatures in the host might lead to a novel means of diagnosing infectious diseases.

Physicians and researchers have known for decades that B. pertussis destroys the ciliated cells in the epithelial lining of the respiratory tract, but they did not know how the hairlike cilia sweep away mucus; when the ciliated cells die, coughing is the only means of clearing the airway. Earlier work had shown that the mediator of this damage is nitric oxide, produced in the respiratory tract in response to tracheal cytotoxin, which is a toxin thought to be responsible for the actual lung damage central to the disease. During FY 1999, researchers demonstrated that mucus-secreting cells are the source of the nitric oxide in response to tracheal cytotoxin and bacterial endotoxin. The production of nitric oxide does not damage the mucus-secreting cells but is devastating to the neighboring ciliated cells responsible for mucus transport in the airways. These findings suggest new possibilities of therapy for pertussis patients, based on interference with the molecular signals involved in generating lung damage.

Plague. Plague is an ancient disease caused by the bacterium Yersinia pestis. This agent is maintained in nature primarily in rodent-flea cycles and occurs throughout many regions of the western United States and many foreign countries. Most humans become infected through the bite of infected fleas associated with wild rodents. Many humans have also acquired the infection and pneumonic plague through aerosol transmission of the bacteria from infected cats. About 20% of people with bubonic plague develop a secondary pneumonia; therefore, the potential for outbreaks of pneumonic plague still exists. Intramural NIAID scientists are investigating how the bacteria adapt to the flea vector and are identifying genes and the proteins they encode that are essential for infection and blockage in fleas. Proteins of the hemin storage locus and Yersinia murine toxin have been identified as potential transmission factors associated with fleabite.

Relapsing Fever. Human relapsing fever is caused by numerous species of spirochetes transmitted primarily by fast-feeding soft ticks or, with one exception, the human body louse. Tick-borne (endemic) relapsing fever occurs in scattered foci throughout the western United States and is characterized by repeated episodes of high fever interrupted by periods of feeling well. Intramural NIAID scientists identified Borrelia hermsii as the cause of a fatal human neonatal case in eastern Washington State. A new serological test was also developed to confirm infection with the louse-borne (epidemic) relapsing fever spirochete B. recurrentis. The complete DNA sequence of the 30-kilobase circular plasmid of B. hermsii was also completed and found to contain many regions homologous to plasmids of similar size in the Lyme disease spirochete.

Syphilis. Syphilis, once a potentially fatal sexually transmitted disease that caused widespread epidemics, is still a major cause of illness and death around the world. In addition, people with syphilis lesions are at higher risk for HIV infection. Although reported syphilis cases in the United States are at an all-time low, outbreaks still occur, especially in inner cities and the rural South. Currently, penicillin G benzathine is the single-dose treatment of choice for syphilis. During FY 1999, researchers found a single dose of azithromycin also prevents syphilis in people exposed to infected sexual partners.

Rare Autoimmune Diseases

Scleroderma. Scleroderma, an autoimmune disease that is more common in women, has many features of graft versus host disease (GVHD), which occurs in recipients of stem cell transplants. Researchers found that maternal cells can persist in their offspring for decades, a form of engraftment called microchimerism. Maternal cells were present in both male and female offspring and were found in about 55% of subjects tested, regardless of whether they suffered from scleroderma. In contrast, fetal cells were previously shown to persist in mothers for decades, and more fetal cells were found in mothers with scleroderma than in mothers without scleroderma. The new findings raise questions about how differing microchimeric cell populations interact in the host and what the consequences of these interactions are for immune tolerance and autoimmunity.

Complement Disorders (Systemic Lupus Erythematosus)

Eighty percent of individuals with genetically defective serum complement proteins also have the autoimmune disease called systemic lupus erythematosus (SLE). Although this group represents a small fraction of total SLE patients, the association of SLE with complement deficiency is unexpectedly strong and has puzzled researchers for years. Recent research results provide a likely explanation for this association and expand insight into mechanisms of immune self-tolerance. Researchers created mouse strains deficient in a specific complement protein or in relevant complement receptors. Remarkably, these complement-deficient mice were found to have mature B cells that could react against self-proteins; in other words, they were not self-tolerant. Complement deficiency in mice genetically prone to autoimmune diseases also results in the spontaneous development of SLE. These findings provide important new insight into the genetic association of human SLE with complement deficiency.

Rare Primary Immunodeficiency Disorders

Bare Lymphocytic Syndrome. Individuals with bare lymphocytic syndrome (BLS) lack expression of all major histocompatiblity complex (MHC) class II gene products on their cells, resulting in deficient immune responses and marked susceptibility to infections. MHC class II molecules stimulate inflammatory or helper T cells by presenting peptides on the surface of an infected cell. BLS is caused by a mutation in the genes that regulate the MHC class II expression, not the MHC genes themselves. In some cases of BLS, an MHC class II transactivator called CIITA is responsible, and in other cases, a protein that binds to the MHC class II promoters, known as RFX, is defective. Researchers have analyzed the most common cause of BLS and demonstrated that, in these patients, BLS is associated with defects in a newly described gene, RFX-B, which is found in the RFX complex; in another study, researchers discovered a 24-amino acid deletion in CIITA in one patient with BLS. Understanding these and other regulators of the MHC class II complex is necessary to enable manipulation of the human immune response to prevent and treat BLS.

Severe Combined Immunodeficiency Disorder. Several combined immunodeficiency disorder (SCID) is a rare and fatal syndrome in which the major immune defenses are lacking. Some children with SCID have lived for years in germ-free rooms and "bubbles." However, a few SCID patients have been successfully treated with transplants of bone marrow, which contains stem cells from which all elements of blood are derived, including platelets, white blood cells (B and T lymphocytes), and red blood cells. To be successfully transplanted, bone marrow from a donor must carry self-markers-a set of genes known as major histocompatibility locus A that is genetically identical to that of the bone marrow recipient. Bone marrow transplantation of genetically nonidentical donors can cause GVHD, which is often fatal. In a recent study, NIAID-supported researchers found that most infants with SCID who received a transplant of bone marrow cleansed of T cells survived, and all of the infants who received histocompatibility locus A-identical marrow from a related donor survived. Few infants with SCID have an histocompatibility locus A-identical donor; therefore, the ability to successfully use parental marrow cleansed of T cells is a significant milestone in the search for a cure.

X-Linked Hyper-IgM Syndrome. Individuals with X-linked hyper-IgM syndrome (XHIM) lack, or have only trace amounts of, several functional classes of antibodies, or immunoglobulins (IgG, IgA, IgE), but have normal or elevated levels of the antibody (IgM), causing them to be highly susceptible to recurrent infections. This disease is caused by a defect in the T-cell surface molecule, CD40 ligand (CD40L), which binds to the B-cell receptor, CD40. This binding is a critical step that causes B cells to switch from IgM production to the secretion of other classes of immunoglobulins. Until recently, the relationship between specific CD40L mutations and XHIM has not been well defined. Now researchers have demonstrated that the inability of a mutant CD40L to bind to the CD40 receptor is the most important predictor of disease severity. Another significant discovery was that mutant CD40L actually inhibits the ability of normal CD40L to activate the CD40 receptor. These results suggest that restoring normal immune function will require large amounts of normal CD40L to overcome the negative effects of mutant CD40L, which may limit the use of gene therapy to correct the disease.

Rare Diseases Research Initiatives

FY 1999 Newly Funded Initiatives in Infectious Diseases

The mycology research unit for program projects resulted in three awards for research on coccidioidomycosis, candidiasis, and cryptococcosis.

FY 1999 Issued Initiatives in Infectious Diseases

  • Therapeutics Research on AIDS-Associated Opportunistic Infections (PA-99-124): to encourage research grant applications aimed at novel approaches to discovery and preclinical development of therapeutic agents against opportunistic infections in people with AIDS. Many of these opportunistic infections are rare diseases.
  • Evolution of Infectious Diseases (GM-99-005): to encourage development of a predictive science of infectious diseases by applying the perspectives, theories, and methods of population and evolutionary biology to important issues of disease emergence, prevention, and treatment.
  • Hepatitis Animal Model Network (RFP 99-19): to broaden the scope of available animal models for screening antivirals to hepatitis B and to focus research efforts on hepadnaviral pathogenesis and immunity in these models. The work scope was written broadly enough to include studies with other hepatitis models, should they be identified.
  • Nonhuman Primate Animal Models for Experimental Research on Chronic Lyme Neuroborreliosis: to provide detailed information on the cellular and molecular mechanisms involved in the pathogenesis of long-term (persistent) infections of the central nervous system (CNS) by B. burgdorferi.

FY 1999 Newly Funded Initiatives in Autoimmunity and Immune Mechanisms

  • NIAID funded seven Research Project Grants under the request for application (RFA) "Hyperaccelerated Award/Mechanisms in Immune Disease Trials." This RFA supports mechanistic studies in clinical trials of immunomodulatory interventions, including trials in primary immunodeficiency diseases. In FY 1999, studies of SCID and DiGeorge syndrome were supported. The NIH Office of Research on Women's Health (ORWH), NIAMS, NIDDK, NHLBI, and NINDS join NIAID as cosponsors.
  • NIAID chairs the Autoimmune Diseases Coordinating Committee, which includes 22 NIH Institutes, Offices, and Centers that support research on autoimmune diseases; FDA; the Veterans Administration; CDC; and private organizations that sponsor research in this area, such as the Sjögren's Syndrome Foundation and the Crohn's and Colitis Foundation of America. In FY 1999, the committee facilitated the funding of seven new trans-NIH initiatives, and nine previously planned or ongoing initiatives received increased support. Selected ongoing initiatives include the Autoimmunity Centers of Excellence, Stem Cell Transplantation for the Treatment of Autoimmune Diseases, and the Multiple Autoimmune Disease Genetics Consortium, which will establish a repository of genetic and clinical data and materials collected from families in which two or more individuals are affected by two or more distinct autoimmune diseases.
  • NIAID and other NIH institutes support the International Histocompatibility Working Group to develop, standardize, and distribute highly sensitive reagents for tissue typing worldwide. The objectives of the working group are to enhance identification of healthy individuals at risk for developing autoimmune disorders and to ensure that transplant recipients receive optimally matched donor organs and tissues.
  • The Primary Immunodeficiency Disease Registry includes information on disease prevalence in the overall population and in various subgroups; the number and types of genetic defects resulting in disease; the clinical spectrum of disease; the correlation between genetic defect and clinical picture; the effects of current therapy; and the causes and incidence of morbidity and mortality.
  • Three program projects and four R01 projects to study basic parameters of human immune responses were funded in the Human Immunology Centers of Excellence.
  • The Immune Tolerance Network is a multi-institutional research program, cosponsored by NIAID, NIDDK, and Juvenile Diabetes Foundation International (JDFI). The network's objective is to accelerate research on immune tolerance through the design and conduct of clinical trials, mechanistic studies and assay development for kidney transplantation, islet transplantation for type 1 diabetes, autoimmune diseases, and asthma and allergic diseases. Statistical, technical, regulatory, clinical trial coordination, monitoring, and administrative expertise will be provided by the Network's Statistical and Clinical Coordinating Center.

FY 1999 Issued Initiatives in Autoimmunity and Immune Mechanisms

  • New Imaging Technologies for Autoimmune Diseases (RFA-AI-99-004): to develop new methods for in vivo imaging of the immune system in small animal models of human autoimmune diseases.
  • Vaccine Immunology Basic Research Centers (RFA-AI-99-008): to support research to address fundamental immune mechanisms as a basis for effective human vaccine development.
  • Innovative Research in Human Mucosal Immunity (RFA-AI-99-011): to fund exploratory/developmental research project grants to attract new investigators and support novel research into understanding the human mucosal immune system.
  • Target Organ Damage in Autoimmune Diseases (RFA-AR-99-003): to support research specifically targeted toward identifying and evaluating cellular and molecular pathways involved in organ damage and the genetic basis of target organ involvement in autoimmunity.
  • Environment/Infection/Gene Interactions in Autoimmune Disease (RFA-ES-99-003): to support basic or population-based research to determine the role of environmental and infectious agents that initiate and/or exacerbate autoimmune diseases.
  • Development of Animal Models of HIV-Related Lung Disease (RFA-HL-99-012): to stimulate development and validation of animal models of HIV-related lung disease and animal-based research in these models.

FY 1999 Cooperative Research and Development Agreements

Cooperative Research and Development Agreements (CRADAs) allow for the assignment of technology, patent, and licensing rights before a collaboration starts. In addition, they provide inventors and their Federal laboratories with a share in the royalties resulting from federally funded research. In FY 1999, NIAID investigators entered into six CRADAs related to rare diseases. Three were with SmithKline Beecham and Chiron Therapeutics for the evaluation of an acellular pertussis vaccine; one was an ongoing CRADA with Protein Design Laboratory for the production and evaluation of human anti-herpes simplex virus monoclonal antibody as a therapeutic agent for the treatment of neonatal herpes; and two were with SmithKline Beecham for the development of hepatitis A and E vaccines.

Rare Diseases-Related Program Activities

In FY 1999, NIAID sponsored numerous workshops on rare diseases to identify research opportunities and to stimulate research and research collaborations on rare diseases and disorders. The five workshops described below were carried out with support from ORD.

  • The goals of the Systemic Sarcoidosis Workshop were (1) to identify the current state of knowledge of sarcoidosis, including the immunological mechanisms underlying this disease and other immunological lung diseases; and (2) to identify knowledge gaps and potential areas for future research. The meeting was sponsored by NIAID, NHLBI, and ORD.
  • The conference New Immunotherapies for Autoimmune Disease brought together bench scientists, clinicians, and patient groups to discuss cutting-edge immunotherapies to treat autoimmune diseases. This meeting featured two symposia, one targeted to a lay audience and one to a scientific audience. The conference was sponsored by NIAID and the American Autoimmune Related Diseases Association, with cosponsorship by ORD; ORWH; NIEHS; NIDDK; NIAMS; NINDS; JDFI; Arthritis Foundation; Crohn's and Colitis Foundation of America; Myositis Association of America; Sjögren's Syndrome Foundation; the National Pemphigus Foundation; Biogen, Inc.; Hoechst Marion Roussel, Inc.; and La Jolla Pharmaceutical Company.
  • At the meeting Discovery of Human Immune Response Genes, participants discussed strategies to expedite the discovery of genetic elements that contribute to the susceptibility to, or protection from, autoimmune and other immune-mediated diseases.
  • Crohn's Disease-Is There a Microbial Etiology? was cosponsored by NIAID, NIDDK, and ORD. The purpose of the conference was to review the current state of knowledge relevant to a microbial etiology of Crohn's disease (CD), a serious, debilitating, inflammatory bowel disease. Participants reviewed evidence for and against the hypothesis that the bacterium Mycobacterium avium subspecies paratuberculosis is the cause of CD and defined needed research that could shed light on the etiology and pathogenesis of this chronic disease.
  • NIAID, in collaboration with CDC, FDA, and ORD, sponsored a conference on The Laboratory Diagnosis of Lyme Disease. The major focus of this conference was to assess the strengths and weaknesses of existing diagnostic methods and to define the type of research needed to develop new, more sensitive diagnostic procedures.

In addition to the workshops and meetings cosponsored with ORD, NIAID held meetings of the Mycoses Study Group, which celebrated 25 years in April, and of both the NIH Lyme Disease Coordinating Committee and the NIAID Lyme Disease Advisory Panel, which reviewed the progress of current clinical studies on the efficacy of antibiotic therapy for the treatment of chronic Lyme disease. During FY 1999, the Collaborative Antiviral Study Group, a multi-institutional collaborative network that conducts clinical trials to evaluate experimental therapies for viral infections, held its annual meeting. Participants reviewed the status of ongoing clinical antiviral studies, learned of new experimental therapeutic opportunities from pharmaceutical representatives, and planned future trials.

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Last Reviewed: January 27, 2005
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