2024 Tolerance and Autoimmunity Lecture Notes PDF

TOLERANCE AND AUTOIMMUNITY Block: Foundations Block Director: James Proffitt, PhD Session Date: Monday, August 26, 2024 Time: 4:00 – 5:00 pm Instructor: Lonnie Lybarger, PhD Department: Cellular & Molecular Medicine Email: lybarger@ariz...

TOLERANCE AND AUTOIMMUNITY Block: Foundations Block Director: James Proffitt, PhD Session Date: Monday, August 26, 2024 Time: 4:00 – 5:00 pm Instructor: Lonnie Lybarger, PhD Department: Cellular & Molecular Medicine Email: [email protected] Instructor: Erika Bracamonte, MD Department:Pathology Email: [email protected] INSTRUCTIONAL METHODS Primary Method: IM13: Lecture ☐ Flipped Session ☐ Clinical Correlations Resource Types: RE18: Written or Visual Media (or Digital Equivalent) INSTRUCTIONS Please read the session objectives and notes prior to session. The notes give additional depth and can be used to supplement the lecture, if needed. Likewise, the recommended readings indicated below can be used as a supplement. READINGS RECOMMENDED Reading: Additional information can be found primarily in chapter 9 of Basic Immunology: Functions and Disorders of the Immune System, 7th ed. (Abbas, Lichtman, and Pillai), 2020, and chapter 6 of Robbins and Kumar Pathologic Basis of Disease, 10th Ed. (Kumar, Abbas, and Aster). These textbooks are available electronically through the Health Sciences library. LEARNING OBJECTIVES: 1. Give the three defining properties needed to establish the presence of an autoimmune disease. 2. List and explain the general features that characterize autoimmune diseases. 3. Explain the difference between central and peripheral tolerance, and describe the basic mechanisms by which immunological tolerance against “self” is established, including clonal deletion, anergy, and the activity of regulatory T cells. 4. Explain how genetics and environment both contribute to the development of autoimmunity. 5. Describe the proposed mechanisms by which tolerance can be broken to produce autoimmunity, including bystander activation, molecular mimicry, release of sequestered antigens, and superantigen-mediated disease induction. 6. For the following autoimmune conditions, describe the basic clinical presentation of each, the major tissues and organs targeted for autoimmune attack, and type(s) of hypersensitivity reaction (immune pathway) involved: Block: Foundations | BRACAMONTE / LYBARGER [1 of 18] TOLERANCE AND AUTOIMMUNITY i. systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome, scleroderma, type I diabetes, Goodpasture syndrome. CURRICULAR CONNECTIONS Below are the competencies, educational program objectives (EPOs), disciplines and threads that most accurately describe the connection of this session to the curriculum. Related Related Competency\EPO Disciplines Threads COs LOs CO-01 LO #1 MK-02: The normal structure and Immunology N/A function of the body as a whole and of each of the major organ systems CO-01 LO #2 MK-05: The altered structure and Pathology N/A function (pathology & pathophysiology) of the body/organs in disease CO-01 LO #3 MK-02: The normal structure and Immunology N/A function of the body as a whole and of each of the major organ systems CO-01 LO #4 MK-02: The normal structure and Immunology N/A function of the body as a whole and of each of the major organ systems CO-01 LO #5 MK-01: Core of basic sciences Immunology N/A MK-05: The altered structure and Pathology function (pathology & pathophysiology) of the body/organs in disease CO-01 LO #6 MK-05: The altered structure and Pathology N/A function (pathology & pathophysiology) of the body/organs in disease CONTEXT: Autoimmune disease – a condition in which the adaptive immune system attacks the body’s own tissues – is common, and since it can affect any organ system, you will encounter examples of autoimmune disease in all blocks of the curriculum. In this lecture, we will explore the mechanisms by which immune tolerance to self-antigens is established and maintained, and proposed mechanisms that lead to a breakdown of tolerance. We will look at the general features of autoimmunity, and clinical features and pathophysiology of some common autoimmune diseases, to illustrate the manifestations of dysregulated immune responses. Block: Foundations | BRACAMONTE / LYBARGER [2 of 18] TOLERANCE AND AUTOIMMUNITY LECTURE NOTES: I. AUTOIMMUNITY OVERVIEW Adaptive immune responses directed against healthy cells and tissues of the body can produce autoimmune diseases. Autoimmunity results from a failure of the mechanisms that generate or maintain self-tolerance. This is generally due to inheritance of susceptibility genes and/or environmental factors. Autoimmune diseases can be organ-specific or can affect many organs (and are then called ‘systemic’). Many people have autoimmune diseases ranging from the relatively benign, to more severe diseases such as rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, and multiple sclerosis. It is estimated that 5% of the people in developed countries have an autoimmune disease, and the incidence is increasing. A suspected case of autoimmune disease must meet these three criteria: 1) Presence of autoimmune reaction. Auto-specific T cells and/or antibodies must be present. 2) The autoimmune response must be the primary source of injury, and not a secondary consequence of another disease process. 3) Absence of other causes for the disease. GENERAL CONCEPTS: Autoimmune Disease is a specific and sustained adaptive immune response directed against self which causes damage to the host. There are more than 80 different autoimmune diseases that affect millions of people worldwide. Collectively, they are a leading cause of disease. Tolerance is the acquired and specific lack of immunological reactivity to an antigen. Experimentally, it is most easily induced in fetal or very young animals. It is the basis for the lack of reactivity to self and can be induced in B cells and T cells. Some general features of autoimmunity: 1. Development of autoimmune disease involves genetic factors and environmental factors. There are many very strong links between particular MHC-I and -II alleles and certain diseases. Likewise, certain Block: Foundations | BRACAMONTE / LYBARGER [3 of 18] TOLERANCE AND AUTOIMMUNITY environmental exposures (such as infections) can precede autoimmunity. 2. Disease frequency differs between sexes, with an overall higher incidence of most diseases in females (80% of autoimmune diseases are diagnosed in females). See table below. 3. Autoimmune diseases ‘wax and wane’ and tend to be progressive. It is thought that many autoimmune phenomena wax and wane due to cycles of immune activation followed by suppression, the latter mediated at least in part by regulatory T cells (Tregs) that suppress auto-antigen-specific effector cells (CD4 and CD8 T cells). It is the nature of the immune response to ‘attack and retreat’. In females, this effect can be related to hormone cycles. In general, the severity of autoimmune diseases increases over time. 4. Mechanisms of tissue injury in autoimmunity are classified according to those for hypersensitivity - at least Types II-IV (Type I pathways are not often implicated in autoimmunity). Some autoimmune diseases have characteristics of more than one hypersensitivity reaction, particularly as the disease progresses. However, the diseases are classified by the INITIAL symptom presentation or the proposed mechanism of pathogenesis (e.g., Type III for immune- complex diseases). 5. There can be overlap in the clinical, pathologic and serologic features of autoimmune diseases, which can make precise diagnosis challenging. Patients may present with evidence of multiple autoimmune diseases. Block: Foundations | BRACAMONTE / LYBARGER [4 of 18] TOLERANCE AND AUTOIMMUNITY Table modified from Fig 13-2 The Immune System 3rd Ed. Sex Differences in Autoimmunity The incidence of many autoimmune diseases is higher in females. The reasons for this are not fully known, but may be due to the effects of sex hormones on immune cells, or gene dosage effects from incomplete X- inactivation in women. These are some ideas that have been proposed. Here is a recent review article on the influence of estrogens on immune cell function: https://doi.org/10.3389/fimmu.2015.00635, along with a recent study regarding X-inactivation: https://pubmed.ncbi.nlm.nih.gov/38306984/ Block: Foundations | BRACAMONTE / LYBARGER [5 of 18] TOLERANCE AND AUTOIMMUNITY Source: CDC (http://wwwnc.cdc.gov/eid/article/10/11/04-0367_article) II. DEVELOPMENT OF AUTOIMMUNE DISEASE - MAKING AND BREAKING TOLERANCE The capacity of lymphocytes to create a vast array of unique receptors for antigen leads to the production of some lymphocytes clones that are self- reactive. Several mechanisms exist to create a T cell and B cell pool that is tolerant to self-antigens. These can be divided into two broad classes: 1. CENTRAL TOLERANCE occurs in the primary lymphoid organs (thymus for T cells and bone marrow for B cells). - Negative selection. T and B cells that express antigen receptors that react strongly to self-antigens can be deleted during their development in the thymus and bone marrow, respectively. Thymic epithelial cells have the unique ability to express a vast number of proteins (potential antigens) that are normally found in peripheral tissues. This allows developing T cells to sample self-antigens via their T cell receptors; self-reactive cells can be deleted. People with defects in this pathway have a range of autoimmune disorders. In addition, developing B cells that are self-reactive can undergo a process called ‘receptor editing’ to create a new antibody molecule specificity that is no longer self-reactive. This involves Block: Foundations | BRACAMONTE / LYBARGER [6 of 18] TOLERANCE AND AUTOIMMUNITY additional V-J gene segment recombination of the Ig light-chains by a given B cell. 2. PERIPHERAL TOLERANCE - Anergy is a state of non-responsiveness that can be induced in T and B cells when they encounter their antigens in a non-stimulatory context, such as conditions of low inflammation, when APCs present antigens on MHC molecules in the absence of do costimulatory molecules. Anergy induction: - Regulatory T cells (Tregs) have the capacity to inhibit the activity of virtually all cells of the immune system, including T and B cells. Negative selection is not completely effective and many auto-reactive T cells (CD4 and CD8) populate the periphery. However, they typically are prevented from becoming activated or fully functional because of the suppressive effects of Tregs. Treg deficiency results in aggressive, multi-organ autoimmunity. - Tregs produce many suppressive factors (such as anti-inflammatory cytokines like IL-10 and TGF-) that inhibit the function of other T cells, as well as virtually all other immune cell types. Block: Foundations | BRACAMONTE / LYBARGER [7 of 18] TOLERANCE AND AUTOIMMUNITY Tregs can be made in the thymus or induced in the periphery. - Some tissues are ‘immune-privileged’, meaning lymphocytes do not typically enter these tissues, and so do not encounter tissue-restricted antigens. The eye is one example. Trauma to the tissue can release antigens that the immune system has never ‘seen’ before. The testes and placenta are also considered immune-privileged. Note that even these tissues must have some capacity for immunity. BREAKING TOLERANCE GENES: 1. HLA (the human MHC locus) is the dominant genetic factor affecting susceptibility to autoimmune disease. Not clear in most cases why individuals with a particular HLA allele develop certain diseases. (‘Relative risk’ = risk of contracting the disease relative to someone without the allele). Note that other non-MHC genes can contribute to autoimmunity. Block: Foundations | BRACAMONTE / LYBARGER [8 of 18] TOLERANCE AND AUTOIMMUNITY Examples of genetic associations with MHC genes and autoimmunity - Though most individuals with ankylosing spondylitis have the HLA-B27 allele, only 2% of people with this allele have the disease. - Studies of mono- versus di-zygotic twins have typically revealed that most autoimmune diseases are more frequent in monozygotic twins. Yet, concordance in monozygotic twins is often well below 100% These findings argue that genes AND environment matter ENVIRONMENT: 2. Bystander Activation of APCs to present self-antigens. During any immune response to a foreign antigen, APCs will present some self- peptides to T cells along with peptides derived from the microbe. Because of the infection and ensuing inflammatory response, the APC may become activated while presenting some self-peptides, thereby activating self-reactive T cells. This phenomenon is sometimes called “bystander activation”. Block: Foundations | BRACAMONTE / LYBARGER [9 of 18] TOLERANCE AND AUTOIMMUNITY 3. Molecular mimicry. Concept: during an infection, T and B cells respond to the infectious agent, leading to recovery. However, certain antigens from the pathogen are similar to self-antigens. The T cells and B cells that respond to the pathogen may therefore become pathogenic because they will also target the self-antigen, leading to tissue destruction. - One example of molecular mimicry is rheumatic fever. Antibodies produced against a Streptococcal antigen cross-react with a myocardial antigen. This is one reason why ‘strep throat’ is treated aggressively with antibiotics, and this practice has greatly reduced the incidence of rheumatic fever in the US. 4. Tissue trauma can result in the release of normally ‘sequestered’ antigens, along with inflammation, providing an opportunity for T cells to become activated against these antigens (such as testis and eye). A rare condition called Sympathetic Ophthalmia occurs when trauma to one eye leads to an autoimmune reaction affecting both eyes (bilateral). 5. Another model to explain induction of autoimmunity is the action of superantigens. Superantigens are exotoxins produced by some species and strains of Stapthylococcus and Streptococcus. These toxins induced massive and antigen-nonspecific activation of CD4 T cells. Some of these T cells could be autoreactive and their activation could lead to autoimmune disease. Treatment for Autoimmune Disease: A number of therapies are used to treat autoimmune diseases, most of which work by blocking the effector pathways involved in a particular disease. The specific pathways are related to the mechanism of tissue damage (Remember: hypersensitivity reactions, especially Types II-IV). Specific treatment information will be discussed in later Blocks, but often involve medications like steroids (glucocorticoids) that reduce immune cell function and inflammation. Block: Foundations | BRACAMONTE / LYBARGER [10 of 18] TOLERANCE AND AUTOIMMUNITY III. PRODUCTION AND ROLE OF AUTOANTIBODIES Production of autoantibodies (antibodies targeting self-antigens) is a common result of loss of self-tolerance and is seen in many autoimmune diseases. Autoantibodies: 1. May recognize cell surface proteins, components of cell cytoplasm, or nuclear components 2. Assist in diagnosis of autoimmune disease - certain autoantibodies are specific/characteristic of certain diseases 3. Can give information as to whether disease is currently active - high titer of autoantibodies in the blood may correlate with more severe disease Antinuclear antibodies (ANA’s) are important autoantibodies present in various autoimmune diseases 1. Directed against nuclear antigens 2. Types: Antibodies to DNA, histones, and non-histone proteins bound to RNA, nucleolar antigens 3. ANA can be characterized by immunofluorescence staining of inflammatory cells. 4. Limitations: About 5-15% of normal individuals have positive ANA (particularly in older age patients) IV. SELECTED EXAMPLES OF AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS Clinical Features: 1. Onset may be acute or insidious, but is a chronic disease - relapsing, remitting 3. Injury is manifested principally in skin, joints, kidney, serosal membranes (pleura, pericardium), CNS 4. Female to male ratio about 9:1; teen-age or young adult predilection 6. African American and Hispanic patients often more severely affected Typical clinical presentation: Teen-aged or young adult female with complaints of skin rash, photosensitivity, joint pain, fever, and hematuria (blood in the urine). Kidney: Variety of forms of glomerulonephritis (abnormalities of renal glomerulus) Skin: Malar (cheeks, bridge of nose) rash Block: Foundations | BRACAMONTE / LYBARGER [11 of 18] TOLERANCE AND AUTOIMMUNITY Autoantibodies in SLE: Against a variety of antigens (especially nuclear antigens, though many other antigens may be targeted) Role of these antigens in pathogenesis is variable, but their presence is very useful in diagnosis and monitoring Pathogenesis of SLE: 1. Genetic factors: Increased risk of family members developing SLE Clinically non-SLE family members may have autoantibodies or other autoimmune diseases 2. Non-genetic factors: Drugs Ultraviolet light Sex hormones, particularly estrogens (pregnancy) Injury/trauma (including surgery) 3. Immunologic factors: Variety of abnormalities of immune system are seen in SLE patients a. Helper T-cells: induce formation of anti-DNA antibodies through B cells b. Type II hypersensitivity: involved in the anti-cellular component of SLE i. Antibodies react against cellular antigens (anti-RBC, anti- WBC, anti-platelet) c. Type III hypersensitivity: formation of DNA-anti-DNA immune complexes, which deposit in tissues and cause injury (e.g., glomerular disease). This is thought to be the primary factor driving SLE. As the disease progresses, other hypersensitivity reactions become involved. Block: Foundations | BRACAMONTE / LYBARGER [12 of 18] TOLERANCE AND AUTOIMMUNITY Model for the immuno-pathogenesis of SLE. In this hypothetical model, susceptibility genes interfere with the maintenance of self-tolerance, and external triggers lead to persistence of nuclear antigens. The result is an antibody response against self nuclear antigens, which is amplified by the action of nucleic acids on dendritic cells (DCs) and B cells, and the production of type I interferons. TLRs, Toll-like receptors. From Robbins and Kumar Basic Pathology, 11th Ed; figure 5.20. Block: Foundations | BRACAMONTE / LYBARGER [13 of 18] TOLERANCE AND AUTOIMMUNITY Treatment: Proven: Corticosteroids, immunosuppressive drugs (Cytoxan) Investigational: Monoclonal antibodies (bind to B cells and inactivate them), plasmapheresis (i.e. plasma exchange) – only for very severe disease RHEUMATOID ARTHRITIS Clinical Features: 1. Chronic inflammatory disease that primarily affects the joints 2. May also involve extraarticular tissues such as the skin, blood vessels, lungs, and heart 3. Primary manifestation is cartilage destruction and proliferation of synovial tissue (pannus) caused by T cells and antibodies reactive with joint antigens, often beginning with small joints of the fingers 4. Typically begins with malaise, fatigue, and generalized musculoskeletal pain in about half of patients; joint involvement develops after weeks to months. The pattern of joint involvement varies, but it is generally symmetrical and affects small joints before larger ones. Pathogenesis of RA: Block: Foundations | BRACAMONTE / LYBARGER [14 of 18] TOLERANCE AND AUTOIMMUNITY Major processes involved in the pathogenesis of rheumatoid arthritis. From Robbins and Kumar Basic Pathology, 11th Ed; figure 26.42. Activated CD4+ T cells release inflammatory mediators that stimulate other inflammatory cells, leading to tissue injury. The primary role of T cells in this disease has caused it to be classified as a Type IV hypersensitivity instead of Type III, though a type III mechanism can contribute to the disease at later stages. Although many cytokine mediators can be isolated from inflamed joints, the most important ones include: IFN-γ from Th1 cells, which activates macrophages and resident synovial cells. IL-17 from Th17 cells that recruits neutrophils and monocytes. Block: Foundations | BRACAMONTE / LYBARGER [15 of 18] TOLERANCE AND AUTOIMMUNITY RANKL, which is expressed on activated T cells and stimulates bone resorption. TNF and IL-1 from macrophages stimulate resident synovial cells to secrete proteases that destroy hyaline cartilage. Of these, TNF has been most firmly implicated in RA pathogenesis, and anti-TNF biologics have revolutionized its treatment. SJÖGREN SYNDROME Clinical Features: 1. Chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting from immunologically mediated destruction of the lacrimal and salivary glands. 2. Most commonly in females between 50 and 60 years of age. Produces blurring of vision, burning, and itching, and thick secretions accumulate in the conjunctival sac. Xerostomia results in difficulty in swallowing solid foods, a decrease in the ability to taste, cracks and fissures in the mouth, and dryness of the buccal mucosa. Parotid gland enlargement is present in one-half of patients. 3. Occurs as an isolated disorder (primary form), also known as the sicca syndrome, or more often in association with another autoimmune disease (secondary form). Pathogenesis of Sjögren syndrome: Initiating mechanism is still unclear, but it is thought that T cells are the main initial drivers of disease, recognizing antigens in these exocrine glands. For this reason, it is probably a Type IV hypersensitivity, initially. B cells and antibodies come to play an important role as the disease progresses; anti-nuclear antibodies are common and can help with diagnosis Intense lymphocytic infiltration of glands is observed, with fibrosis and atrophy in later stages There may be a link between viral infection of these glands and development of this autoimmune disease SYSTEMIC SCLEROSIS (SCLERODERMA) Clinical Features: 1. Chronic inflammation thought to be the result of autoimmunity 2. Widespread damage to small blood vessels, leading to tissue ischemia 3. Progressive interstitial and perivascular fibrosis in the skin and multiple organs. 4. Skin manifestation is observed first; other organs can become involved as the disease progresses over several years. The majority of patients have diffuse, sclerotic atrophy of the skin, which usually begins in the fingers and distal regions of the upper extremities (‘sclerodactyly’) and extends proximally to involve the upper arms, shoulders, neck, and face. Block: Foundations | BRACAMONTE / LYBARGER [16 of 18] TOLERANCE AND AUTOIMMUNITY Pathogenesis of systemic sclerosis Initiating events are not well understood, but T-Helper 2 CD4+ T cells are thought to be important, producing TGF-beta and IL-13. These cytokines drive a pro-fibrotic response. This is most aligned with a Type IV hypersensitivity mechanism. The dermis becomes very thick with dense type I collagen deposition Small arteries in affected areas may show thickening of the basal lamina, endothelial cell damage, and partial occlusion. A model for the pathogenesis of systemic sclerosis. Unknown external stimuli cause vascular abnormalities and immune activation in genetically susceptible individuals, and both contribute to the excessive fibrosis. From Robbins and Kumar Basic Pathology, 11th Ed; figure 6.30. TYPE I DIABETES Clinical Features: 1. Commonly develops in childhood and is typically diagnosed by the time of puberty. 2. Initial symptoms include excessive thirst (polydipsia), excessive urination (polyuria), weight loss, and hyperglycemia. Unmanaged disease can lead to diabetic ketoacidosis 3. Hyperglycemia and hypoinsulinemia are evident Pathogenesis of type I diabetes Disease results from progressive destruction of insulin-producing pancreatic beta cells Several beta cell antigens can be targeted by auto-reactive T cells, including insulin. Thus, a Type IV hypersensitivity mechanism is the likely primary driver of this disease. Block: Foundations | BRACAMONTE / LYBARGER [17 of 18] TOLERANCE AND AUTOIMMUNITY CD4 and CD8 T cells are implicated in beta cell destruction Antibodies against beta cell antigens can develop, even before the appearance of symptoms (before enough beta cells are lost to produce clinical signs), and these can be useful in monitoring disease progression. There is some suggestion that certain viral infections may serve as environmental triggers of the disease via molecular mimicry. GOODPASTURE SYNDROME Clinical Features: 1. Typically presents as rapidly progressing glomerulonephritis (hematuria, proteinuria), with roughly half of patients also showing pulmonary hemorrhage (shortness of breath, cough, and even bloody cough (hemoptysis)). 2. Initial presentation of malaise, weight loss, fever, or arthralgia, of relatively short duration (a few weeks, at most). Pathogenesis of Goodpasture syndrome Circulating antibodies (primarily IgG) against type IV collagen (alpha-3 chain) Type IV collagen is present in basement membranes throughout the body and exists as a heterotrimer of alpha chains; there are 6 different alpha chains in humans. The alpha-3 chain of type IV collagen is especially enriched in the basement membranes of the capillaries in glomeruli and lung alveoli Antibody binding to the antigen activates complement, leading to formation of the membrane attack complex and recruitment of leukocytes (especially neutrophils). This is a type II hypersensitivity mechanism causing microvascular pathology. Block: Foundations | BRACAMONTE / LYBARGER [18 of 18]