4. Anti-erythrocyte Antibodies Cause Type II Autoimmunity
5. Goodpasture's Syndrome
6. Autoimmune Diseases Arise When Tolerance to Self-antigens is Lost
7. Diseases Mediated by Antibodies Against Cell-surface Receptors
8. Autoimmune Diseases of Endocrine Gland
9. Auto-antibodies Again TSH Receptor
10. Temporary Symptoms of Anti-mediated Autoimmune Disease
11. Hashimoto Thyroiditis
12. Comparison of Histological Sections
13. Auto-antibodies Against the Acetylcholine Receptor
14. Pemphigus Foliaceus
15. How Antibodies Against Desmoglein Cause Skin Blistering
16. Every Autoimmune Disease Resembles a Type II, III, or IV Hypersensitivity Reaction
17. Deposition in Immune Complexes
18. Systematic Lupus Erythematosus
19. Inflamed Joints
20. The Effects of Treatment
21. Correlation Between Thymus Involution and Rheumatoid Arthritis
22. Antibodies Against Streptococcal Cell-wall Antigens
23. Physical Trauma
24. The Mechanism of Celiac Disease
25. Comparison of Healthy and Celiac Intestinal Mucosa
26. Recap
Autoimmune diseases are classified as Types II, III, and IV because their tissue-damaging effects are like those of the corresponding hypersensitivity reactions. This table shows some Type II autoimmune diseases that are caused by antibody against cell-surface or matrix antigen.
This table lists some Type III and Type IV autoimmune diseases. Type III or immune complex diseases are listed in the top portion of the table, while Type IV are cell-mediated autoimmunity and listed in the bottom portion. Systemic lupus erythematosus (SLE) is caused by antibody to DNA, and histones, ribosomes, small nuclear RNA (snRNA), and small cytoplasmic ribonucleo-protein (scRNP). SLE and other autoimmune diseases will be presented in more detail later in this lecture.
These images show the destruction of erythrocytes that are coated with anti-erythrocyte autoantibodies. The lower left panel shows that erythrocytes opsonized with IgG can be bound and destroyed by phagocytosis by phagocytes that have FcγR. The lower middle panel shows the effect of complement fixation and the binding of the erythrocytes by phagocytes via the complement receptor CR1 as well as via the FcγR binding the antibody. The lower right panel shows that complement fixation on the erythrocyte surface can also lead to complement-mediated lysis of the opsonized erythrocyte.
These images show sections of a renal corpuscle in serial biopsies taken from a patient with Goodpasture’s syndrome, which is a form of Type II autoimmunity. The antibody is directed to a non-collagenous of basement membrane collagen Type IV. Panel A shows the glomerulus stained for IgG deposition by immunofluorescence. Antibody against glomerular basement membrane is deposited in a linear fashion, as shown by the green fluorescence along the glomerular basement membrane. The autoantibody causes the local activation of cells bearing Fc receptors, the activation of complement, and the influx of neutrophils. Panel B, hematyxylin and eosin staining of a section through a renal corpuscle shows that the glomerulus is compressed by the formation of a crescent, as indicated by the letter C of proliferating mononuclear cells within the Bowman’s capsule that is indicated by the letter B, and that there is an influx of neutrophils as indicated by the letter N into the glomerular tuft.
This image shows the symptoms of a condition called Autoimmune Poly-Endocrinopathy-Candidiasis-Ectodermal Dystrophy, (APECED). Such visible symptoms of the disease can help in the diagnosis of children with APECED. which is an inherited autoimmune glandular disease, or APD. The course of the disease is heterogeneous as it involves various genes, as well as environmental factors. In Finnish, the autoimmunity syndrome is associated with chronic infection with Candida.
Autoimmune disease can be caused by agonistic or by antagonistic antibodies. In Grave’s disease, the antibody binding to thyroid stimulating hormone receptor is agonistic, and causes hyperthyroidism. In Myasthenia gravis, the antibody to acetylcholine receptor blocks its activity, and hence, is said to be antagonistic. In Insulin-resistant diabetes, the antibody binding to insulin receptor is antagonistic, and hence, causes hyperglycemia and ketoacidosis. In hypoglycemia, is caused by agonistic antibody that binds to insulin receptor.
This table provides a description of autoimmune diseases of endocrine glands. The glandular organs that are affected include the thyroid gland, islets of Langerhans cells in the pancreas, and the adrenal gland.
This figure illustrates the action of antibodies against thyroid-stimulating hormone (TSH) in causing Grave’s disease. In the left half of the figure, thyroid epithelial cells make thyroglobulin, a glycoprotein that is stored in follicles formed by the spherical arrangement of thyroid cells. Iodide represented as green circles is taken up and used to iodinate and cross-link tyrosine residues of thyroglobulin. The upper right panel shows that normally when thyroid hormones are needed, the pituitary gland produces TSH which binds to the TSH receptor on thyroid cells, inducing the endocytosis of TSH and breakdown of iodinated thyroglobulin, with release of the thyroid hormones tri-iodothyronine or T3, and thyroxine or T4. The T3 and T3 that are produced signal the pituitary gland to stop releasing TSH. The lower right panel shows that in Grave’s disease, anti-TSH receptor autoantibodies bind to the TSH receptor of thyroid cells, mimicking TSH and inducing the continuous synthesis and release of thyroid hormones. In patients with Grave’s disease, the production of thyroid hormone becomes independent of the presence of TSH and of the body’s requirements for thyroid hormones.
These panels depict Grave’s disease being transmitted from mother to fetus. In this case, a mother has Grave’s disease and Grave’s ophthalmopathy, which causes her eyes to bulge. IgG auto-antibodies against TSH receptor (TSHR) pass from the mother to the fetus in utero and binds to TSH receptor on thyrocyte, thus passively gives the baby a temporary Grave’s disease that disappears with the degradation of maternal IgG in the infant’s circulation. It is recommended to remove the autoantibody by total exchange of blood plasma by plasmapharesis.
Hashimoto Thyroiditis is another autoimmune disease of the thyroid gland. Hashimoto thyroiditis is an autoimmune disease that is manifested by a destruction of thyroid cells caused by CD4 Th1 response, which produces both effector CD4 T cells and production of antibody to thyroid antigens. Infiltration of lymphocytes causes a progressive destruction or the normal thyroid tissue and the loss of thyroid hormone. Panel A shows that in a health thyroid gland, the epithelial cells form spherical follicles containing thyroglobulin. Panel B shows that in patients with Hashimoto’s thyroiditis, the thyroid gland becomes infiltrated with lymphocytes which destroy the normal architecture of the thyroid gland and can become organized into structures resembling secondary lymphoid tissue, called ectopic lymphoid tissues. Panel C shows a schematic diagram of lymphoid tissue within the thyroid gland. Hashimoto thyroiditis becomes a hypothyroid disease, but the inflammation causes the gland to be swollen.
These images show a section of the pancreas in a healthy person compared to that in a patient with Type 1 diabetes. Panel A is a micrograph of a healthy human pancreas, showing a single islet. The islet is the discrete light-staining area in the center of the photograph. It is composed of hormone-producing cells, including the β cells that produce insulin. Panel B shows a micrograph of an islet from a patient with acute onset of Type 1 diabetes. The islet shows insulitis, an infiltration of lymphocytes from the islet periphery toward the center. The lymphocytes are the clusters of cells with darkly staining nuclei. Both tissue sections are stained with hematoxylin and eosin.
Now we are going to find out how auto-antibodies to acetylcholine receptors can cause myasthenia gravis. Myasthenia gravis is an autoimmune disease in which signaling from nerve to muscle across the neuromuscular junction is impaired. As a result, patients with myasthenia gravis suffer from muscle weakening, starting with droopy eyelids and followed by double vision, facial muscle weakness, chest muscle weakness which impairs breathing, resulting in susceptibility to respiratory infection that can cause death. The upper panel shows that in a healthy neuromuscular junction, signals generated in nerves trigger the release of acetylcholine, which binds to the acetylcholine receptors of the muscle cells, causing an inflow of sodium ions that indirectly causes muscle contraction. The lower panel shows that in patients with myasthenia gravis, auto-antibodies specific for the acetylcholine receptor reduce the number of receptors on the muscle-cell surface by binding to the receptors and causing their endocytosis and degradation. Consequently, the efficiency of the neuromuscular junction is reduced, which is manifested as muscle weakening.
This figure is a schematic diagram of desmoglein, which is a cell-surface protein with five extracellular domains annotated as EC1 and EC5. Desmoglein is an adhesion molecule in the cell junctions that holds keratinocytes together. Auto-antibodies to desmoglein cause skin disease, including pemphigus foliaceus. The autoimmune response starts by making harmless antibodies against the EC5 domain; over time, the response can spread to make antibodies against the EC1 and EC2 domains. These antibodies cause disease and are of the IgG4 isotype, which has unique characteristics. Pemphigus foliaceus causes blisters, which usually begin on your face and scalp and later, erupt on your chest and back, usually aren’t painful. They tend to be crusty and itchy.
In the early phase of the autoimmune response to desmoglein, antibodies are made against epitopes of the EC5 domain. The left panel shows that these epitopes are not accessible to antibody in functional membrane-associated desmoglein, but the antibodies can bind to soluble degradation products of desmoglein. The center panel shows that soluble immune complexes of antibody desmoglein bound and processed by B cells specific for epitopes of EC1 and EC2 domains. This causes epitope spreading in the later phase of the autoimmune response and the synthesis of high-affinity IgG4 antibodies specific for the EC1 and EC2 epitopes. These epitopes of membrane-associated desmoglein are accessible to antibody, which interferes with the physiological adhesive interactions of desmoglein that are necessary for maintaining skin integrity. The right panel shows that consequently, the antibodies cause the outer layers of the skin to separate, giving blisters.
Systemic lupus erythematosus is a chronic inflammatory disease that can affect any of the major organ systems, and hence causing multiple clinical symptoms. Historically, this butterfly-shaped rash was first used to define and diagnose the disease. Now that the disease is defined immunologically, it is recognized that a proportion of patients who have the disease do not get the rash.
Lupus nephritis. Panel A shows a section through a glomerulus of a patient with SLE. Deposition of immune complexes causes thickening of the basement membrane. In panel B, a similar kidney section is stained with fluorescent anti-immunoglobulin antibodies, revealing the presence of immunoglobulin in the basement membrane deposits. Panel C is an electron micrograph of part of a glomerulus. Dense protein deposits are seen between the glomerular basement membrane and the renal epithelial cells. Neutrophils (N) are also present, attracted by the deposited immune complexes.
In patients with SLE, an ever-broadening immune response is made against nucleoprotein antigens such as nucleosomes, which consist of histones and DNA and are released from dying and disintegrating cells. The left panel shows how the emergence of a single clone of autoreactive CD4 T cells can lead to a diverse B-cell response to nucleosome components. The T cell in the center is specific for a specific peptide represented as red circles from linker histone H1, which is present on the surface of the nucleosome. The B cells at the top are specific for epitopes on the surface on a nucleosome, on H1 and DNA, respectively, and thus bind and endocytize intact nucleosomes, process the constituents, and present the H1 peptide to the helper T cell. Such B cells will be activated to make antibodies, which in the case of the DNA-specific B cell, will be anti-DNA antibodies. The B cell at the bottom right is specific for an epitope on histone H2, which is hidden inside the intact nucleosome and is thus inaccessible to the B-cell receptor. This B cell does not bind the nucleosome and does not become activated by the H1-specific helper T cell. A B-cell-specific for another type of nucleoprotein particle, the ribosome, which is composed of RNA and specific ribosomal proteins, will not bind nucleosomes in the bottom left and will not be activated by the T cell. In reality, a T cell interacts with one B cell at a time, but different members of the same T-cell clone will interact with B cells of different specificity.
The right panel shows the broadening of the T-cell response to the nucleosome. The H1-specific B cell in the center has processed an intact nucleosome and is presenting a variety of nucleosome-derived peptide antigens on its MHC class II molecules. This B cell can activate a T cell specific for any of these peptide antigens, which will include those from the internal histones H2, H3, and H4 as well as those from H1. This H1-specific B cell will not activate T cells specific for peptide antigens of ribosomes because ribosomes do not contain histones.
In summary, left panel shows the specificity of BCR, which binds only to one epitope of the antigen, and the effector cells from a given B cell only produce antibody binding to that epitope. The right panel shows that as an APC, B cell can process antigen complex and present different peptides in association with MHC-II, meaning that one B cell has the potential to interact with different CD4 T cells, and activate them.
Rheumatoid arthritis is the most common disease affecting 1-3% of the US population, with women outnumbering men by 3 to 1. More than 90% of patients with SLE suffer from arthritis. The synovium of an arthritis joint is infiltrated with leucocytes, including neutrophils, macrophages, CD4 and CD8 T cells, B cells, lymphoblasts, and plasma cells, making rheumatoid factor consisting of IgM, IgG, and IgA-specific for the Fc region of IgG.
Rheumatoid arthritis is treated with antibodies that target the inflammatory cytokine TNF-a and B cells. Three parameters are measured, as shown in the three panels.
Left panel: Level of C-reactive protein
Center panel: Swollen joints
Right panel: Pain
The values for patients given a placebo treatment are depicted by the blue curve and the values for patients treated with anti-TNF-a antibody are depicted by the red curve. The results show that the blocking of TNF-a by body antibody decreases the CRP level, as well the swelling of the joints and pain.
This schematic diagram shows that with age there is an inverse correlation between the decreasing capacity of the thymus to make new T cells and the increasing incidence of rheumatoid arthritis.
Autoimmune disease can also be caused by cross-reactive anti-bacterial antibody. The immune response to the bacteria produces antibodies against various epitopes of the bacterial cell surface. Some of these antibodies colored in yellow cross-react with the heart epitopes, whereas others, colored in blue, do not. An epitope in the heart colored in orange is structurally similar but not identical to a bacterial epitope colored in red.
Sympathetic ophthalmia is caused by autoimmune effector cells and auto-antibodies. If a punch in the face ruptures an eye, proteins unique to the eye drain from the anterior chamber to the local lymph node and there, induce an autoimmune response. On occasion, the damaged eye is attacked by autoimmune effector cells and auto-antibodies and become blind. In this case, the undamaged eye also becomes accessible to the same cells and antibodies, a condition called sympathetic ophthalmia.
In celiac disease, inflammation of the small intestine is caused by a CD4 T-cell response. Celiac disease is an inflammatory disease of the intestinal mucosa, which is caused by the immune response to the gluten proteins of wheat flour or the related protein of barley and rye. The first panel shows the digestion of gluten by digestive enzyme leaving an undigested fragment. The second panel shows the entry of the fragment in gut tissue and its deamination by transglutaminase. The third panel shows the presentation of deaminated peptides by DC to naïve CD4 T cell. The fourth panel shows the production of inflammatory cytokines by activated effector T cells, causing tissue damage in the small intestine. Persistent intake of gluten causes chronic inflammation, resulting in the atrophy of the intestinal villi, malabsorption of nutrients and diarrhea. The disease is attributable to genetic predisposition, as well as environmental factors. 80% of people with celiac disease have the HLA-DQ2 allotype and most of the rest have HLA-DQ8.
These images show damaged villi in celiac intestinal mucosa. The left panel shows the surface of the normal small intestine which is folded into finger-like villi, and which provide and extensive surface for nutrient absorption. The right panel shows that in celiac disease, the inflammation and immune response damage the villi. There is a lengthening and increased cell division in the underlying crypts to produce new epithelial cells. There are greater numbers of lymphocytes in the epithelial layer and an increase in effector CD4 T cells, plasma cells, and macrophages in the lamina propria. The damage to the villi reduces the person’s ability to utilize food and can cause life-threatening malabsorption and diarrhea.
Disruption of Healthy Tissue by the Adaptive Immune Response