Autoimmunity
Simply stated, autoimmune disease is caused by failure of the tolerance processes described in the previous section. According to the NIH, up to 8% of the population is affected by one of more than 80 different autoimmune diseases. In certain cases the damage to self cells or organs is caused by antibodies; in other cases, T cells, or both T cells and antibodies, are the culprit. Often chronic and debilitating, these diseases can lead to morbidity and mortality from complications, including prolonged medical intervention.
Autoimmune diseases result from the destruction of self proteins, cells, and organs by auto-antibodies or self-reactive T cells. In 1957, Deborah Doniach (Figure 16-4) and colleagues working in London were the first to theorize, and later show, that serum antibodies from patients with Hashimoto’s thyroiditis reacted against normal thyroid components. This was the first organ-specific autoimmune disease to be characterized, breaking the spell surrounding the controversy over whether self reactivity was even possible. Doniach and co-workers were also responsible for identifying an autoimmune factor that was involved in juvenile diabetes, also known as type 1 diabetes (T1D), another organ-specific autoimmune disease. Rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE, or lupus) are other examples of all too common autoimmune diseases. Table 16-1 lists several of the more prevalent autoimmune disorders, as well as their primary immune mediators.
FIGURE 16-4 Deborah Doniach. Doniach and colleagues were the first to show that antibodies against normal components of the thyroid were to blame for Hashimoto’s thyroiditis.
| Disease | Self antigen/Target gene | Immune effector |
|---|---|---|
| ORGAN-SPECIFIC AUTOIMMUNE DISEASES | ||
| Addison’s disease | Adrenal cells | Auto-antibodies |
| Autoimmune hemolytic anemia | RBC membrane proteins | Auto-antibodies |
| Goodpasture’s syndrome | Renal and lung basement membranes | Auto-antibodies |
| Graves’ disease | Thyroid-stimulating hormone receptor | Auto-antibodies (stimulating) |
| Hashimoto’s thyroiditis | Thyroid proteins and cells | TH1 cells, auto-antibodies |
| Idiopathic thrombocytopenic purpura | Platelet membrane proteins | Auto-antibodies |
| Type 1 diabetes mellitus | Pancreatic beta cells | TH1 cells, auto-antibodies |
| Myasthenia gravis | Acetylcholine receptors | Auto-antibodies (blocking) |
| Myocardial infarction | Heart | Auto-antibodies |
| Pernicious anemia | Gastric parietal cells; intrinsic factor | Auto-antibodies |
| Poststreptococcal glomerulonephritis | Kidneys | Immune complexes |
| Spontaneous infertility | Sperm | Auto-antibodies |
| SYSTEMIC AUTOIMMUNE DISEASES | ||
| Ankylosing spondylitis | Vertebrae | Immune complexes |
| Multiple sclerosis | Brain or white matter | TH1 cells and TC cells, auto-antibodies |
| Rheumatoid arthritis | Connective tissue, IgG | Auto-antibodies, immune complexes |
| Scleroderma | Nuclei, heart, lungs, gastrointestinal tract, kidneys | Auto-antibodies |
| Sjögren’s syndrome | Salivary glands, liver, kidneys, thyroid | Auto-antibodies |
| Systemic lupus erythematosus (SLE) | DNA, nuclear protein, RBC and platelet membranes | Auto-antibodies, immune complexes |
| lmmune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome | Multiorgan/loss of FoxP3 gene | Missing regulatory T cells |
| Autoimmune polyendocrine syndrome type 1 (APS-1) | Multiorgan/loss of AIRE gene | Defective central tolerance |
Autoimmune diseases are often categorized as either organ-specific or systemic, depending on whether they affect a single organ or multiple systems in the body. Another method of grouping involves the immune component that does the bulk of the damage: T cells versus antibodies. In this section, we describe several examples of both organ-specific and systemic autoimmune disease. In each case, we discuss the antigenic target (when known), the causative process (either cellular or humoral), and the resulting symptoms. When available, examples of animal models used to study these disorders are also considered (Table 16-2). Finally, we touch on the factors believed to be involved in induction or control of autoimmunity, and treatments for these conditions.
| Animal model | Possible human disease counterpart | Inducing antigen | Disease transferred by T cells |
|---|---|---|---|
| Spontaneous autoimmune diseases | |||
| Nonobese diabetic (NOD) mouse | Type 1 diabetes (T1D) | Unknown | Yes |
| (NZB × NZW) F1 mouse | Systemic lupus erythematosus (SLE) | Unknown | Yes |
| Obese-strain chicken | Hashimoto’s thyroiditis | Thyroglobulin | Yes |
| Experimentally induced autoimmune diseases* | |||
| Experimental autoimmune myasthenia gravis (EAMG) | Myasthenia gravis | Acetylcholine receptor | Yes |
| Experimental autoimmune encephalomyelitis (EAE) | Multiple sclerosis (MS) | Myelin basic protein (MBP); proteolipid protein (PLP) | Yes |
| Autoimmune arthritis (AA) | Rheumatoid arthritis (RA) | Mycobacterium tuberculosis (proteoglycans) | Yes |
| Experimental autoimmune thyroiditis (EAT) | Hashimoto’s thyroiditis | Thyroglobulin | Yes |
Some Autoimmune Diseases Target Specific Organs
Autoimmune diseases are caused by immune-stimulatory lymphocytes or antibodies that recognize self components, resulting in cellular lysis and/or an inflammatory response in the affected organ. Gradually, the damaged cellular structure is replaced by connective tissue (fibrosis), and the function of the organ declines. In an organ-specific autoimmune disease, the immune response is usually directed to a target antigen unique to a single organ or gland, so the manifestations are largely limited to that organ. The cells of the target organs may be damaged directly by humoral or cell-mediated effector mechanisms. Alternatively, anti-self antibodies may overstimulate or block the normal function of the target organ.
Hashimoto’s Thyroiditis
In Hashimoto’s thyroiditis, an individual produces auto-antibodies and sensitized TH1 cells that are specific for thyroid antigens. This disease is much more common in women, often striking in middle age (see Clinical Focus Box 16-2 for a discussion of sex differences in autoimmune disease). Antibodies are formed against a number of thyroid proteins, including thyroglobulin and thyroid peroxidase. Binding of the auto-antibodies to these proteins interferes with iodine uptake, leading to decreased thyroid function and hypothyroidism (decreased production of thyroid hormones). The resulting delayed-type hypersensitivity (DTH) response is characterized by an intense infiltration of the thyroid gland by lymphocytes, macrophages, and plasma cells, which form lymphocytic follicles and germinal centers (see Chapter 15). These collections of leukocytes can sometimes coalesce into spontaneous lymph node–like assemblies, called tertiary lymphoid organs. The ensuing inflammatory response causes a goiter, or visible enlargement of the thyroid gland, a physiological response to local inflammation caused by antibodies against thyroid-specific proteins. This immune attack leads to decreased function of the gland and symptoms such as fatigue, lethargy, and unexplained weight gain. Replacement therapy involving daily administration of thyroxine, the hormone secreted by the thyroid gland, usually yields good results and allows people to live a normal life. Again, this autoimmune disease is more common in women and the cause is largely unexplained.
Type 1 Diabetes
Type 1 diabetes (T1D), also known as insulin-dependent diabetes mellitus (IDDM), affects almost 2 in 1000 children in the United States; roughly double the incidence observed just 20 years ago. It is seen mostly in youth under the age of 14 and is less common than type 2, or non–insulin-dependent, diabetes mellitus. T1D is caused by an autoimmune attack against insulin-producing cells (beta cells) scattered throughout the pancreas, which results in decreased production of insulin and consequently increased levels of blood glucose. The disease begins with cytotoxic T lymphocyte (CTL) infiltration and activation of macrophages, frequently referred to as insulitis (Figure 16-5), which leads to a cell-mediated DTH response, with resulting cytokine release and the production of auto-antibodies. The subsequent beta-cell destruction is thought to be mediated by cytokines released during the DTH response and by lytic enzymes released from the activated macrophages. Auto-antibodies specific for beta cells may contribute to cell destruction by facilitating either antibody-mediated complement lysis or antibody-dependent cell-mediated cytotoxicity (ADCC) (see Chapter 12).
FIGURE 16-5 Insulitis in Type 1 diabetes. Photomicrographs of an islet of Langerhans in (a) the pancreas from a normal mouse and (b) the pancreas from a mouse with a disease resembling insulin-dependent diabetes mellitus. Note the lymphocyte infiltration into the islet (insulitis) in (b).
The abnormalities in glucose metabolism associated with T1D result in serious metabolic problems that include ketoacidosis (accumulation of ketone, a breakdown product from fat) and increased urine production. The late stages of the disease are often characterized by atherosclerotic vascular lesions (which cause gangrene of the extremities due to impeded vascular flow), renal failure, and blindness. If untreated, death can result. The most common therapy for T1D is daily administration of insulin. Although this is helpful, sporadic doses are not the same as metabolically regulated, continuous, and controlled release of the hormone. Unfortunately, T1D can remain undetected for many years, allowing irreparable loss of pancreatic tissue to occur before treatment begins. Recently, novel transplantation approaches studied in mice have yielded exciting advances in the control of glycemia. If this can be translated to the clinic it could hold promise as a cure for this disease.
One of the best-studied animal models of this disease is the nonobese diabetic (NOD) mouse, which spontaneously develops a form of diabetes that resembles human T1D. This disorder also involves lymphocytic infiltration of the pancreas and destruction of beta cells, and is strongly associated with certain MHC alleles. Disease is mediated by bone marrow–derived cells; normal mice reconstituted with an injection of bone marrow cells from NOD mice will develop diabetes, and healthy NOD mice that have not yet developed disease can be spared by reconstitution with bone marrow cells from MHC-matched normal mice. NOD mice housed in germ-free environments show a higher incidence of diabetes compared with those in regular housing, suggesting that a diverse flora (most likely intestinal) may help block development of autoimmune disease. There is also evidence in humans that perturbations of gut flora are associated with T1D. In genome-wide scans, over 20 insulin-dependent diabetes (Idd) loci associated with disease susceptibility have been identified, including at least one member of the TNF receptor family.
Myasthenia Gravis
Myasthenia gravis is the classic example of an autoimmune disease mediated by blocking antibodies. A patient with this disease produces auto-antibodies that bind the acetylcholine receptors (AChRs) on the motor end plates of muscles, blocking the normal binding of acetylcholine and inducing complement-mediated lysis of the cells. The result is a progressive weakening of the skeletal muscles (Figure 16-6). Ultimately, the antibodies cause the destruction of the cells bearing ACh receptors. The early signs of this disease include drooping eyelids and inability to retract the corners of the mouth. Without treatment, progressive weakening of the muscles can lead to severe impairment in eating as well as problems with movement. However, with appropriate treatment, this disease can be managed quite well and afflicted individuals can lead a normal life. Treatments are aimed at increasing acetylcholine levels (e.g., using cholinesterase inhibitors), decreasing antibody production (using corticosteroids or other immunosuppressants), and/or removing antibodies (via plasmapheresis: the removal and exchange of blood plasma).
FIGURE 16-6 Mechanism of myasthenia gravis induction. In myasthenia gravis, binding of auto-antibodies to the acetylcholine receptor (AChR) (right) blocks the normal binding of acetylcholine (burgundy dots) and subsequent muscle activation. In addition, the anti-AChR auto-antibody activates complement, which damages the motor end plate of the muscle; the number of acetylcholine receptors declines as the disease progresses.
One of the first autoimmune disease animal models was discovered serendipitously in 1973, when rabbits immunized with AChRs purified from electric eels suddenly became paralyzed. (The original aim was to generate monoclonal antibodies specific for eel AChRs that could be used for research.) These rabbits developed antibodies against the foreign AChR that cross-reacted with their own AChRs. These auto-antibodies then blocked muscle stimulation by acetylcholine at the synapse and led to progressive muscle weakness. Within a year, study of this animal model, called experimental autoimmune myasthenia gravis (EAMG), led to the discovery that auto-antibodies to the AChR were also the cause of myasthenia gravis in humans.
Some Autoimmune Diseases Are Systemic
With systemic autoimmune diseases, autoreactive cells recognize a target antigen or antigens found in multiple tissues or organs. This leads to inflammation and physiologic disruptions at multiple, sometimes unconnected, locations in the body. Alternatively, systemic autoimmune disease can be caused by a disruption in regulation or control of tolerance. These diseases arise because the ever-present anti-self cells are no longer held in check. In either case, tissue damage can be widespread and driven by cell-mediated immune activity, auto-antibodies, accumulation of immune complexes, or combinations of these.
Systemic Lupus Erythematosus
One of the best examples of a systemic autoimmune disease is systemic lupus erythematosus (SLE, or lupus). Like several of the other autoimmune syndromes, this disease is more common in women than in men, with an approximately 9:1 ratio (see Clinical Focus Box 16-2). SLE symptoms typically appear between 20 and 40 years of age, and occur more frequently in African American and Hispanic women than in Whites, for unknown reasons. In identical twins where one suffers from SLE, the other has up to a 60% chance of developing SLE, suggesting a genetic component. However, although close relatives of a patient with SLE are 25 times more likely to contract the disease, still only 2% of these individuals ever develop SLE.
Affected individuals may produce auto-antibodies to a vast array of cells or common cellular components, such as DNA and histones, as well as clotting factors, RBCs, platelets, and even leukocytes. Signs and symptoms include fever, weakness, arthritis, kidney dysfunction, and frequently skin rashes, especially the characteristic butterfly rash across the nose and cheeks (Figure 16-7). Auto-antibodies specific for RBCs and platelets can lead to complement-mediated lysis, resulting in hemolytic anemia and thrombocytopenia, respectively. When immune complexes of auto-antibodies with various nuclear antigens are deposited along the walls of small blood vessels, a type III hypersensitivity reaction develops (see Chapter 15). The complexes activate the complement system and generate membrane-attack complexes and complement fragments (C3a and C5a) that damage the walls of the blood vessels, resulting in vasculitis and glomerulonephritis (see Chapter 5). In severe cases, excessive complement activation produces elevated serum levels of certain complement fragments, leading to neutrophil aggregation and attachment to the vascular endothelium. Over time, the number of circulating neutrophils declines (neutropenia) and occlusions of various small blood vessels develop (vasculitis), which can lead to widespread tissue damage. Laboratory diagnosis of SLE involves detection of anti-nuclear antibodies (a common feature), which can be directed against DNA, nucleoprotein, histones, or nucleolar RNA. Indirect immunofluorescence staining, using serum from patients with SLE, produces a characteristic nuclear-staining pattern (Figure 16-8) and yields a presumptive positive diagnosis.
FIGURE 16-7 Systemic lupus erythematosus (SLE or lupus). Representational drawing of a man with characteristic lupus “butterfly” rash over the cheeks and nose.
FIGURE 16-8 Diagnostic test for SLE. Serum dilutions from a patient are mixed with cells attached to a glass slide. Fluorescently labeled secondary antibodies directed against human antibodies are then added and reveal staining of the nucleus, and thus presence of anti-nuclear antibodies, under a fluorescence microscope.
The study of animal models of SLE has yielded much insight into this disease, including the role of specific genes in creating a balance of regulatory-to-effector lymphocytes. While there are several excellent models, the New Zealand mouse remains the oldest and most well-characterized spontaneous model system. F1 hybrids of New Zealand Black (NZB) and New Zealand White (NZW) mice spontaneously develop a severe autoimmune syndrome that closely resembles human SLE, although each of the parent strains displays only mild or variable autoimmune symptoms. NZB/W F1 mice develop autoimmune hemolytic anemia between 2 and 4 months of age, at which time various auto-antibodies can be detected, including antibodies to erythrocytes, nuclear proteins, DNA, and T lymphocytes. As in human SLE, the incidence of autoimmunity in F1 mice is greater in females than in males.
Multiple Sclerosis
Multiple sclerosis (MS) is the most common cause of neurologic disability associated with disease in Western countries. MS occurs in women approximately 3 times more frequently than in men (see Clinical Focus Box 16-2). This difference between the sexes represents an increase from two decades ago, when the ratio was more like 2:1, suggesting that recent increases in the incidence of MS have been primarily in women. Like SLE, MS frequently develops in young to middle adulthood, from 20 to 40 years of age, although the incidence in younger women is also on the rise. Individuals with this disease produce autoreactive CD4+ T cells, with TH17 cells and the IL-17 they secrete as a hallmark. These cells recruit other cells to the site, encouraging inflammatory foci along the myelin sheath of nerve fibers in the brain and spinal cord. Since myelin functions to insulate the nerve fibers, a breakdown in the myelin sheath leads to numerous progressive neurologic dysfunctions, ranging from numbness in the limbs to paralysis or loss of vision. The most frequent form of the disease manifests as “relapsing and remitting”—flare-ups, interspersed with periods of partial recovery—although a chronic, progressive form of the disease is also seen.
MS has both genetic and environmental associations, although the cause of the disease is not well understood. In addition to alleles at the DRB1 locus of MHC class II, which have long been recognized for their association, genome-wide studies in MS-affected families have identified many other potential loci connected to this autoimmune disease, some with immune function. Genetic influence is strong but not absolute; while the average person in the United States has about a 1 in 1000 chance of developing MS, this increases to 1 in 20 for siblings and to 1 in 4 for an identical twin. Epidemiological studies indicate that MS is most common in the Northern Hemisphere, especially in the United States. Relocation from low- to high-incidence regions during early years imparts higher risk of disease. These data suggest that, in addition to strong genetic affects, an environmental component early in life has profound impact on the risk of contracting MS. Infection with certain viruses, especially Epstein-Barr virus (EBV), has long been cited as a possible explanation for this geographic gradient, although recent data suggest more region-specific or lifestyle factors, some related to the hygiene hypothesis (see Chapters 1 and 15). The environmental factors that may impact MS susceptibility include diet, smoking, obesity or BMI, and exposure to sunlight. The latter is likely associated with vitamin D levels and could explain the increasing south-to-north gradient of susceptibility. Interestingly, vitamin D is a known immune modulator that can promote anti-inflammatory responses. Many leukocytes, including T cells, have vitamin D receptors.
Experimental autoimmune encephalomyelitis (EAE) is one of the best-studied animal models of autoimmune disease, and a rodent model for MS. This disease is mediated solely by T cells and can be induced in a variety of species by immunization with myelin basic protein (MBP) or proteolipid protein (PLP)—both components of the myelin sheaths surrounding neurons in the CNS. Within 2 to 3 weeks, the animals develop cellular infiltration of the CNS, resulting in demyelination and paralysis. Most of the animals will become paralyzed and can die. Others have milder symptoms, some with a chronic form of the disease that resembles relapsing and remitting MS in humans. Recent work in this model has highlighted the increasingly appreciated role of diet and the microbiome in disease susceptibility. Germ-free mice are less susceptible to induction of EAE, and addition of particular gut commensals has been shown to either exacerbate or attenuate disease. Studies in patients with MS have likewise noted disruption in the gut flora associated with flare-ups. This small-animal model of the disease has provided an important system for testing causal hypotheses as well as treatments for MS.
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a fairly common autoimmune disorder, most often diagnosed between the ages of 40 and 60 and, again, more frequently seen in women. This autoimmune disease also has a strong genetic susceptibility component and, as with SLE, the HLA-DRB1 locus is implicated, along with many non-MHC genes. The major symptom is chronic inflammation of the joints (Figure 16-9), although the hematologic, cardiovascular, and respiratory systems are also frequently affected. Most individuals with RA produce antibodies that react with citrullinated protein antigens (where an arginine residue is converted to the nonstandard amino acid citrulline), as well as a group of auto-antibodies called rheumatoid factors (RFs). The latter are specific for the Fc region of IgG—in other words, antibodies against antibodies! The classic rheumatoid factor is an IgM antibody, although any isotype can participate. When RFs bind to normal circulating IgG, immune complexes form and are deposited in the joints. These can activate the complement cascade, resulting in a type III hypersensitivity reaction and chronic inflammation of the joints. Like SLE and MS, this systemic autoimmune disease has recently been connected with body flora. In particular, RA is associated with gum disease and the bacteria that cause gingivitis, as well as with smoking. Some believe that these environmental triggers may influence the level of citrullination of proteins in the mucosa, triggering or exacerbating the production of these anti-self antibodies in individuals who are already susceptible to RA.
FIGURE 16-9 Rheumatoid arthritis. Swollen and painful joints are a common symptom of rheumatoid arthritis.
Systemic Autoimmunity Due to Disruptions in Immune Regulation
In the past two decades, a whole new category of disease with autoimmune association has been characterized, linked to genetic disruptions in the regulation of immune function. The two classic examples are autoimmune polyendocrine syndrome type-1 (APS-1) (previously called APECED) and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. These two share many features, despite disruption to separate genes: both are monogenic disorders (caused by a single gene), impact multiple organs, and display the same range of immunopathologies (endocrine dysfunction, autoimmunity, and primary immune deficiency). How can disruption to a single gene result in both too much immune response (directed against self; autoimmunity) and not enough (immune deficiency)? The answer is disruption to homeostatic immune regulation, or a break in self tolerance. APS-1 is caused by mutations in the AIRE gene, critical for central tolerance in the thymus (and possibly elsewhere). The AIRE transcription factor ensures that tissue-specific antigens are expressed in the thymus during T-cell development. This ensures both the elimination of T cells with receptors that recognize tissue-specific antigens and engagement or selection of regulatory T (TREG) cells. IPEX is caused by mutations in the FoxP3 gene, the master transcriptional regulator associated with regulatory T cells, which are generated both during central (tTREG cells) and peripheral tolerance (pTREG cells). In other words, absence of regulatory T-cell function and a disruption to self tolerance are the common denominator.
Both Intrinsic and Extrinsic Factors Can Favor Susceptibility to Autoimmune Disease
Overzealous immune activation can lead to autoimmunity, while suboptimal immune stimulation results in insufficiency that can allow microbes to take control. But what tips the balance toward a break in tolerance and the development of autoimmunity? Experiments with germ-free mouse models, discordance data in identical twins, and epidemiologic studies of geographic associations all suggest roles for both the environment and genes in susceptibility to the development of autoimmunity. In the gene category, alleles in the HLA locus take top prize, as well as several repeat offenders in the immune response category. In terms of environment, lifestyle influences have increasingly entered the picture. Of late, the association of a range of autoimmune diseases with metabolic disruptions (linked to diet, exercise, obesity, and even stress) and an imbalance of microbial flora, especially early in life, are taking center stage.
The Role of Genes in Autoimmunity
Genetically, we are all very, very similar. However, a few small nucleotide differences at key locations can sometimes make a big difference. In the field of autoimmunity, that key location is the MHC locus, thanks to the primary role of its products in determining what fragments of antigens will be presented to T cells. For this reason, particular class I and II alleles or mutations are commonly associated with particular autoimmune diseases. However, we also know that these MHC variants are not the whole story, because two individuals can have exactly the same set of MHC alleles (monozygotic, or identical, twins) and still be discordant for the development of autoimmune disease. This means that while genetics may predispose us to autoimmune susceptibility, one or more factors in the environment must pull the trigger.
The strongest association between an HLA allele and autoimmunity is seen in ankylosing spondylitis (AS). AS is an inflammatory disease of vertebral joints, which is associated with expression of the allele HLA-B27. Expression of this MHC class I allele increases the risk of developing AS by 90-fold. This does not imply causation; most individuals who express HLA-B27 will not develop AS, suggesting additional susceptibility factors and/or triggers. Research conducted in AS-affected families has unearthed additional associations with genes that encode three cytokines connected to TH17 function (IL-12, IL-17, and IL-23), suggesting a potential role for this cell subset in the development of AS. Interestingly, unlike many other autoimmune diseases, AS is more common in men.
It is no surprise that other non-MHC immune genes are also associated with autoimmune disease. As noted previously, inactivating mutations in two genes involved in establishing and maintaining tolerance, AIRE and FoxP3, have strong associations with systemic autoimmune disease (see also Chapters 8 and 18). Many other genes with more subtle or even cumulative effects on susceptibility to autoimmunity have also been discovered. Genes for cytokines and their receptors, antigen processing and presentation, C-type lectin receptors, signaling pathways, adhesion molecules, and costimulatory or inhibitory receptors have all been linked to specific autoimmune diseases (Table 16-3). In many instances, multiple genes plus compounding environmental factors collaborate in autoreactive responses. In some cases, a single gene can heighten susceptibility to multiple different disorders. For instance, a mutant form of the tyrosine phosphatase PTPN22, which dampens TCR signaling capacity, has been linked to T1D, RA, and SLE. It is believed that attenuation of TCR signaling during positive and negative selection in the thymus may be what predisposes carriers of this allele to autoimmune disorders.
| Disease | C-type lectin | Cytokines, their receptors and regulators | Innate immune response | Adhesion and costimulation | Antigen processing and presentation |
|---|---|---|---|---|---|
| Type 1 diabetes (T1D) | CLEC16A | IL-2R | CTLA4 | VNTR-Ins, PTPN22 | |
| Rheumatoid arthritis (RA) | DCIR | STAT4 | REL, C5-TRAFI | CD40 | PTPN22, MHC2TA |
| Ankylosing spondylitis (AS) | IL-1A, IL-23R | KIR complex | ERAP1 | ||
| Multiple sclerosis (MS) | CLEC16A | IL-2RA, IL-7R | CD40 | ||
| Systemic lupus erythematosus (SLE) | STAT4, IRF5 | TNFAIP3 | TNFSF4 | PTPN22 | |
| Crohn’s disease | CLEC16A | IL-23R | NOD2, NCF4 | TNFSF15 | PTPN2 |
Environmental Factors Favoring the Development of Autoimmune Disease
Genetic background, especially immune-related, and sex clearly play a role in susceptibility to autoimmune disease. Likewise, some role of the environment in tipping this genetic predisposition toward disease is fairly universal. In the last decade, in addition to the other environmental suspects (obesity, smoking, infection, etc.), diet and the mucosal flora have jumped onto the stage.
Autoimmune syndromes are more common in certain geographic locations or in particular climates. This suggests a link between environmental and/or lifestyle factors, and the development of autoimmune disease. For example, we know that certain gut microbes (sometimes called our “old friends”) or their secreted products make contact with immune cells in the intestinal mucosa and elsewhere on body surfaces. This communication and negotiation between gut microflora and host cells does not stay local, it “goes viral,” so to speak, helping to regulate peripheral tolerance and suppress autoimmune disease in distant locales. For example, animals maintained in germ-free environments, where even healthy, benign commensals are absent, show heightened susceptibility to autoimmune disease compared with their “microbe-laden” counterparts. How commensal microbes might influence tolerance and autoimmunity is an exciting and fruitful new area of research, and the topic of Clinical Focus Box 16-1.
Infections may also influence the induction of autoimmunity, which could explain some of the geographic disparities. For example, tissue pathology following infection may result in the release of sequestered self antigens that are presented in a way that fosters immune activation rather than tolerance induction. Likewise, the molecular structures of certain microbes may share chemical features with self components, resulting in the activation of immune cells with cross-reactive potential. Since local climate, flora, and fauna help determine which infectious agents can thrive in that environment, geography could be a surrogate for certain infections that serve as autoimmune triggers in the right genetic background.
The Role of Certain T Helper Cell Types in Autoimmunity
In both organ-specific and systemic autoimmunity, CD4+ more than CD8+ T cells have been linked to instigation of disease. As we know from Chapter 10, characteristics of the antigen, the status of the APC to make first encounter, and the surface receptors used during this engagement set the stage for which pathway will be chosen in the transition from innate to adaptive immunity. In this transition, the cytokine milieu will help determine which subsets of a TH cell predominate. The induction of autoimmunity is likewise a complex process, where even experimental models of the same human disease can be induced by different means, making outcomes in each case difficult to correlate. Nevertheless, a few themes have emerged from both human and animal studies of autoimmune disease.
Much of the initial data collected from various studies of autoimmune disease supported a role for autoreactive TH1 cells and IFN-γ. For example, IFN-γ levels in the CNS of mice with EAE correlate with the severity of disease, and treatment with this cytokine exacerbates MS in humans. Likewise, adoptive transfer of IFN-γ-producing CD4+ TH cells from mice with EAE can induce disease in naïve hosts. On the flip side, elimination of IFN-γ, by means of neutralizing antibodies or by removal of the gene, does not protect animals from EAE; in fact, it worsens the symptoms.
These conflicting results led to the study of other cytokines or T-cell types that may be involved in the induction of autoimmunity, especially those connected to IFN-γ. Recall from Chapter 10 that IL-12 and IL-23, which can be produced by APCs during activation, encourage the production of other cytokines, such as either IFN-γ or IL-17, favoring T-cell development along the TH1 or TH17 pathway, respectively. Studies have shown that mice engineered to lack the gene for the p40 subunit of IL-12, which happens to be shared with IL-23, are protected from EAE. This protection is due to inhibition of IL-23, a cytokine required to sustain TH17 cells. Mice lacking IL-17A are less susceptible to both EAE and collagen-induced arthritis, a model for human RA. In subsequent studies of patients with MS, RA, and psoriasis (another autoimmune disorder), elevated IL-17 expression has been found at the site of inflammation, and increased serum levels of IL-17 and IL-23 have been observed in patients with SLE. Collectively, these findings support the notion that TH17 cells may be an important driver of multiple autoimmune diseases. Not surprisingly, this has led to new trials of immunotherapy designed to manipulate the TH17 pathway in individuals affected by these autoimmune syndromes.
What Causes Autoimmunity?
As we have just seen, specific genetic and environmental predisposing factors have strong and predictable impacts on susceptibility to autoimmunity. Sex differences in autoimmune susceptibility, preferentially affecting women, must also be considered (see Clinical Focus Box 16-2). Factors that may account for this include hormonal differences between the sexes, plus the impact of conception and pregnancy. Of late, differences between the sexes in terms of microflora, especially after puberty, are also under study. A heightened appreciation for the evolutionarily conserved role of our microbiome in tuning systemic immunity should not be underestimated (see Chapter 13), and advances in this area are likely to have profound impacts on our understanding of and treatments for many autoimmune diseases. Finally, random (stochastic) events also take their toll. Although not very satisfying, in most cases a complex and nuanced combination of these is likely at fault for autoimmune induction.
Recall that V(D)J recombination is random. Even in identical twins these processes will play out in unique ways. This means we all live with a very different set of antigen-specific T-cell and B-cell receptors, even monozygotic twins. For T cells, activation requires pAPCs presenting self MHC in association with unique antigen fragments, which will depend on the haplotype of the individual. Over half of all antigen-specific receptors recognize self proteins, yet not all of the T cells bearing them are deleted during negative selection. Many will be selected as tTREG cells, all following a nuanced set of interconnected pathways in the thymus. At the end of this, surviving self-reactive T and B cells in the periphery should be held in check by anergic or regulatory mechanisms, but of course they are also susceptible to daily environmental influences. Exposure to carcinogens or infectious agents that favor DNA damage or polyclonal activation can interfere with this regulation and/or lead to the expansion and survival of rare T- or B-cell clones with autoimmune potential (Table 16-4). Acquired mutations in genes that could favor expansion include those encoding antigen receptors, signaling molecules, costimulatory or inhibitory molecules, apoptosis regulators, or growth factors (see Table 16-3). Gram-negative bacteria, cytomegalovirus, and Epstein-Barr virus are all known polyclonal activators, inducing the proliferation of numerous clones of B cells, different in every person, that express IgM in the absence of T-cell help. If B cells reactive to self antigens are activated by this mechanism, auto-antibodies can appear. Finally, since body flora, especially at mucosal surfaces, is a known regulator of systemic immune cells, from birth to death, the fluctuations in our microbiome can be creating fluctuations in our immune status. Collectively, this regulated chaos suggests that the control over autoreactivity may be a daily, uphill battle!
| Group | Examples | Disease association examples |
|---|---|---|
| Infection | Viral | Type 1 diabetes |
| Bacterial | Reiter’s syndrome | |
| Fungal | Autoimmune polyendocrine syndrome type 1 (APS-1) | |
| Toxins | Smoking | Rheumatoid arthritis |
| Fabric dyes | Scleroderma | |
| Iodine | Thyroiditis | |
| Stress | Psychological | Multiple sclerosis, systemic lupus erythematosus (SLE) |
| Oxidative, metabolic | Rheumatoid arthritis | |
| Ultraviolet light | SLE | |
| Endoplasmic reticulum (ER) stress | Ulcerative colitis | |
| Food | Gluten | Celiac disease |
| Breastfeeding cessation | Type 1 diabetes | |
| Gastric bypass | Spondyloarthropathy |
An association between specific microbial agents and autoimmunity has been postulated for several reasons beyond the potential for DNA damage or polyclonal activation. As discussed earlier, some autoimmune syndromes are associated with certain geographic regions, and immigrants to an area can acquire enhanced susceptibility to the disorder associated with that region. This, coupled with the fact that a number of viruses and bacteria possess antigenic determinants that are similar in structure to host-cell components, led to a hypothesis known as molecular mimicry. This hypothesis posits that some pathogens express protein epitopes resembling self components, either in conformation or primary sequence, and when these enter the body they inadvertently activate self-reactive cells in a proinflammatory microenvironment, bypassing immune regulation.
For instance, rheumatic fever, an autoimmune disease that can lead to destruction of heart muscle cells and joints, can develop a few weeks after infection with group A Streptococcus. In this case, antibodies to streptococcal antigens have been shown to cross-react with the heart muscle proteins, resulting in a type II hypersensitivity reaction with immune complex deposition and complement activation (see Chapter 15). In a separate study, 600 different monoclonal antibodies specific for 11 different viruses were evaluated for their reactivity with normal tissue antigens. More than 3% of the virus-specific antibodies tested also bound to normal host tissue, suggesting that molecular similarity between foreign and host antigens may be fairly common. In these cases, susceptibility may also be influenced by the MHC haplotype of the individual, since certain MHC class I and MHC class II molecules may be more effective than others in presenting cross-reactive peptides for T-cell activation.
Release of sequestered antigens is another proposed path to autoimmune initiation, one that may also be connected with environmental exposures. The induction of self tolerance in T cells results from exposure of immature thymocytes to self antigens in the thymus, followed by clonal deletion or inactivation of most self-reactive cells (see Chapter 8). Tissue antigens that are not expressed in the thymus will not engage with developing T cells and will thus not induce self tolerance. In thymic medullary epithelial cells expressing the AIRE transcription factor, tissue-specific antigens are expressed randomly and typically at very low levels, and some may not be expressed at all. Peripheral tolerance should cover these as well, but trauma to tissues following an accident, surgery, or an infection can release these tissue-specific antigens. For instance, the release of heart muscle antigens following myocardial infarction (heart attack) can lead to the formation of auto-antibodies that target healthy heart muscle cells. Studies involving injection of normally sequestered antigens directly into the thymus of susceptible animals support this proposed mechanism: injection of CNS myelin proteins or pancreatic beta cells can inhibit the development of EAE or diabetes, respectively. In these experiments, exposure of immature T cells to self antigens normally not present in the thymus, or present at low levels, presumably boosted central tolerance to these antigens.
In summary, it is worth reiterating that, although certain events may be associated with the development of autoimmunity, a complex combination of genotype, environmental exposures, and random events likely influences the balance of self tolerance versus autoimmune disease induction.
Treatments for Autoimmune Disease Range from General Immune Suppression to Targeted Immunotherapy
Ideally, treatment for autoimmune diseases should reduce or suppress only the autoreactive cells and molecules, leaving the rest of the immune system unaffected. Implementing this precision approach has proven difficult. Current therapies to treat autoimmune disease fall into three categories: broad-spectrum immunosuppressive treatments, immunosuppression directed at specific cells or pathways, and targeted immunotherapy aimed at guiding the host immune cells toward a new and more beneficial pathway (Table 16-5). In this section, these are discussed in relative order, from the most general to the most targeted. As one might expect, the magnitude and range of side effects follow suit.
| Name | Brand name | Mechanism of action | Target disease/Syndrome |
T- OR B-CELL–DEPLETING AGENTS |
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| Lymphocyte immune globulin (horse), anti-thymocyte globulin (rabbit) | ATGAM (horse), Thymoglobulin (rabbit) | Depleting horse/rabbit polyclonal anti-thymocyte antibody | Renal transplant rejection; aplastic anemia |
| Muromonab (OKT3) | Orthoclone OKT3 | Mouse anti-human CD3 mAb; depleting | Acute transplant rejection; graft-versus-host disease (GvHD) |
| Zanolimumab | HuMax-CD4 | Human anti-CD4 mAb, partially depleting | Rheumatoid arthritis (RA) |
| Rituximab (IDEC-C2B8) | Rituxan | Chimeric anti-CD20 mAb; depleting | RA |
TARGETING TRAFFICKING/ADHESION |
|||
| Fingolimod (FTY720) | Gilenya | S1P receptor agonist; stimulating | Relapsing/remitting multiple sclerosis (MS); renal transplant rejection |
TARGETING TCR SIGNALING |
|||
| Cyclosporin A | Gengraf, Neoral, Sandimmune | Calcineurin inhibitor | Transplant rejection; active RA; severe plaque psoriasis |
| Tacrolimus (FK506) | Prograf (systemic), Protopic (topical) | Calcineurin inhibitor | Transplant rejection; atopic dermatitis; ulcerative colitis (UC); RA; myasthenia gravis; GvHD |
TARGETING COSTIMULATORY AND ACCESSORY MOLECULES |
|||
| Abatacept (BMS-188667) | Orencia | Fc fusion protein with extracellular domain of CTLA-4; blocks CD28-CD80/86 interaction | RA; lupus nephritis; inflammatory bowel disease (IBD); juvenile idiopathic arthritis (JIA) |
| Belatacept (BMS-224818, LEA29Y) | Nulojix | Same as Abatacept, higher affinity | Transplant rejection |
TARGETING CYTOKINES/CYTOKINE SIGNALING |
|||
| Sirolimus | Rapamune | mTOR inhibitor | Renal transplant rejection; GvHD |
Broad-Spectrum Therapies
Most first-generation therapies for autoimmune diseases are broad-spectrum immune suppressants. These are not cures but do reduce symptoms and provide the patient with an acceptable quality of life. Corticosteroids, azathioprine, cyclophosphamide, and methotrexate are all strong anti-inflammatory drugs. They suppress lymphocytes fairly indiscriminately, by inhibiting their survival and proliferation, or by killing rapidly dividing leukocytes. While this can work to inhibit overall inflammation throughout the body, side effects are significant and sometimes long-lasting. These include general cytotoxicity, often to all rapidly dividing cells (e.g., hair follicles, intestinal lining, blood cells), an increased risk of uncontrolled infection, and even the development of cancer.
In some autoimmune diseases, removal of a specific organ or set of toxic compounds can alleviate symptoms. Patients with myasthenia gravis often have thymic abnormalities (e.g., thymic hyperplasia or thymomas), in which case thymectomy can increase the likelihood of remission. Plasmapheresis may also provide significant if short-term benefit for diseases involving antigen-antibody complexes (e.g., myasthenia gravis, SLE, and RA), where removal of a patient’s plasma antibodies temporarily eliminates autoreactive antibodies and the resulting immune complexes.
Strategies That Target Specific Cell Types
When antibodies and/or immune complexes are heavily involved in autoimmune pathology, strategies aimed at killing or blocking B cells can improve clinical symptoms. For example, a monoclonal antibody against the B cell–specific antigen CD20 (rituximab) depletes a subset of B cells and provides short-term benefit for patients with RA. However, most cell type–specific agents used to treat autoimmune disorders also need to target T cells or their products, because these cells are either directly pathogenic or provide help to autoreactive B cells.
The first anti–T-cell antibodies used to treat autoimmune disease targeted the CD3 molecule and were designed to deplete T cells without signaling through this receptor. Although somewhat effective in the treatment of T1D, this method still induced broad-spectrum immune suppression. The moderately more specific anti-CD4 antibodies successfully reversed MS and arthritis in animal models, although human trials of this treatment have shown no efficacy. A possible reason for this failure is that anti-CD4 also likely interferes with the activity of CD4+CD25+ regulatory T cells, a cell type we know is key to regulating tolerance and inhibiting autoimmunity.
With this in mind, and with the discovery of the TH17 subset, scientists are beginning to target specific helper T-cell pathways. In several mouse models of autoimmunity, including MS, T1D, SLE, and IPEX, the transfer of TREG cells can clearly inhibit disease pathogenesis. The greatest difficulty with translating this from mouse to human is in selecting a population of TREG cells to transfer, as FoxP3 in humans does not correlate well with immunosuppressive activity. Therefore, most of the emphasis in the clinical applications of this approach is currently directed toward mimicking TREG-like mechanisms of suppression (e.g., using IL-10) or inhibiting the TH17 cells because of their known role in autoimmune disease (e.g., by using IL-17 or IL-23 blocking antibodies).
Therapies That Block Specific Steps in the Inflammatory Process
Since chronic inflammation is a hallmark of debilitating autoimmune disease, individual steps in the inflammatory process are potential targets for intervention. These would be more targeted then broad-spectrum anti-inflammatories and might therefore spare some arms of the immune response to still work to protect us from foreign invaders. Drugs that block TNF-α, one of the early mediators in most autoimmune inflammatory processes, are widely used to treat RA, psoriasis, and Crohn’s disease. An IL-1 receptor antagonist is also approved for treatment of RA, as are antibodies directed against the IL-6 receptor and IL-15. Other anti-inflammatory, cytokine-based experimental treatments for autoimmunity include targeting the IL-2 receptor (CD25 and CD122), IL-1, and various IFNs. All of these have some side effects that overlap with broad-spectrum anti-inflammatory drugs, plus they are much more expensive.
More broadly, the class of drugs designated as statins, and used by millions to reduce cholesterol levels, has been found to lower serum levels of C-reactive protein (CRP). This acute-phase protein is an indicator of inflammation. Reduced levels of CRP can inhibit proinflammatory cytokines and decrease expression of adhesion molecules on endothelial cells, reducing many of the symptoms of most autoimmune diseases. Clinical trials of statins for the treatment of RA and MS have shown encouraging results. The addition of such drugs with prior FDA approval and extensive safety testing is a tremendous advantage, considering that 95% of agents fail human trials because of safety concerns.
Compounds that block the chemokine or adhesion molecule signals controlling lymphocyte movement into sites of inflammation can also thwart autoimmune processes. The most well-characterized inhibitor of cell trafficking is fingolimod (or FTY720). This compound is an analog of sphingosine and induces internalization of sphingosine 1-phosphate (S1P) receptors in the body, which are involved in the migration of lymphocytes into the blood and lymph nodes (see Chapters 8 and 9). This inhibits egress of all subsets of T cells, resulting in a reduction of up to 85% in circulating blood lymphocytes. So far it has been effective in treating MS, where it has also been reported to inhibit TH1 and TH17 cells, and to enhance TREG-cell activity. A compound with similar outcomes, natalizumab, is a monoclonal antibody specific for the adhesion molecule α4 integrin and has also been approved for the treatment of MS. This molecule is involved in lymphocyte homing to the brain. However, natalizumab is not without its problems; at least 500 patients, most of whom were treated for 2 years or more, have developed a life-threatening CNS infection. This side effect is believed to stem from enhanced mobilization and infection of B cells harboring the JC virus, which causes this brain infection.
Therapies That Interfere with Costimulation
As we saw in Chapter 10, T cells require both antigenic stimulation via the TCR (signal 1) and costimulation (signal 2) to become fully activated. Without costimulation, T cells undergo apoptosis, become anergic, or are selected as regulatory cells to become specific immune inhibitors. Therefore, one way to control the activation of specific T cells would be to regulate or block costimulation. CTLA-4 is a potent inhibitor of T-cell activity, binding to CD80/86 with an affinity that is approximately 20 times greater than that of CD28, its costimulatory counterpart. To this end, a fusion protein was generated consisting of the extracellular domain of CTLA-4 combined with the human IgG1 constant region; it is called CTLA-4Ig. This therapeutic fusion protein drug, Abatacept (marketed as Orencia), was approved for the treatment of RA and is designed to block CD80/86 on APCs from engaging with CD28 on T cells, inhibiting costimulation. This drug has also been studied with limited success in patients with MS and inflammatory bowel disease, but results in patients with SLE have been more disappointing.
Antigen-Specific Immunotherapy
The holy grail of immunotherapy to treat autoimmune disease is a strategy that specifically targets just the autoreactive cells, sparing all other leukocytes and their actions. In this ideal world, clinical therapies that could specifically induce tolerance to an auto-antigen might reverse the course of autoimmune disease. In order to manipulate the antigen-specific tolerance process one would need to introduce the specific antigen in question, ideally in a tolerogenic form or context. However, even when the auto-antigen is well characterized, as with T1D and MS, introduction of a self antigen “reworked” to be viewed as a tolerogen carries the risk of exacerbating the disease. In fact, this was seen in some of the first trials using this approach. Nonetheless, glatiramer acetate (GA, or Copaxone), a polymer of four basic amino acids found commonly in myelin basic protein (MBP), has been approved for treating MS. Although it seems to shift the TH population toward an increase in the number of TREG cells and to modulate the function of APCs, it has shown only modest improvement over standard therapies for this disease.
Several other compounds that act as immunotherapy treatments for autoimmune disorders are in earlier stages of development, and some look quite promising. For example, Francisco Quintana and co-workers in Boston are exploring a novel immunotherapy approach for the treatment of T1D, using nanoparticles coated with both proinsulin, one of the target antigens in T1D, and a molecule that can deliver a tolerogenic signal to APCs. In vitro, treatment of murine DCs with these nanoparticles induced a tolerogenic phenotype, suppressed proinflammatory cytokine production, and led to differentiation of T cells into a regulatory phenotype. More importantly, they found that administration of these coated nanoparticles to NOD mice blocked spontaneous development of diabetes. If strategies such as this can be successfully applied to humans, there may be new hope for antigen-specific immunotherapy in the treatment of a host of autoimmune diseases.