# Lecture 23: Autoimmunity II: Major Autoimmune Diseases

## Immunology

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## Learning Objectives

By the end of this lecture, students will be able to:

1. Classify autoimmune diseases as organ-specific or systemic
2. Describe the immunopathogenesis of systemic lupus erythematosus (SLE)
3. Explain the immune mechanisms underlying rheumatoid arthritis (RA)
4. Describe the pathogenesis of multiple sclerosis (MS) and the role of autoreactive T cells
5. Explain the autoimmune destruction of pancreatic beta cells in type 1 diabetes (T1D)

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## Lecture Content

### I. Classification of Autoimmune Diseases

Autoimmune diseases can be broadly divided into two categories based on the distribution of the target antigens. **Organ-specific autoimmune diseases** involve immune attack directed against antigens confined to a single organ. Examples include type 1 diabetes, in which the immune system targets the pancreas; Hashimoto's thyroiditis and Graves' disease, which affect the thyroid; multiple sclerosis, which targets the central nervous system; myasthenia gravis, which disrupts the neuromuscular junction; and autoimmune hemolytic anemia, in which red blood cells are destroyed.

In contrast, **systemic autoimmune diseases** involve immune responses against widely distributed antigens, resulting in multi-organ involvement. Classic examples include systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, Sjogren's syndrome, and dermatomyositis.

Despite their diversity, autoimmune diseases share several common features. They tend to follow a chronic, relapsing-remitting or progressive course. Genetic susceptibility plays a major role, particularly through HLA associations, and most are polygenic. There is a notable female predominance, with an overall ratio of approximately 2-3:1 female to male, though some diseases reach ratios as high as 9:1. Environmental triggers such as infections, UV light, smoking, and the microbiome contribute to disease initiation. Finally, the hallmarks of these diseases are the presence of autoantibodies and/or autoreactive T cells.

### II. Systemic Lupus Erythematosus (SLE)

Systemic lupus erythematosus is the prototypic systemic autoimmune disease, characterized by multi-organ involvement affecting the skin, joints, kidneys, central nervous system, blood, and serous membranes. It predominantly affects women of childbearing age, with a female-to-male ratio of 9:1, and has a higher prevalence in African American, Hispanic, and Asian populations.

The central immunopathogenic feature of SLE is the **loss of tolerance to nuclear antigens**, including dsDNA, histones, nucleosomes, Sm, RNP, Ro/SSA, and La/SSB. A critical mechanism driving this loss of tolerance is **defective clearance of apoptotic cells**. Complement deficiency, particularly in C1q, C2, and C4, impairs the clearance of apoptotic debris, leading to accumulation of nuclear antigens. C1q deficiency has the strongest single-gene association with SLE, as approximately 90% of individuals with this deficiency develop a lupus-like disease. Similarly, DNase I deficiency results in failure to degrade extracellular DNA.

The accumulated nuclear debris triggers **innate immune activation**. DNA and RNA from dying cells activate plasmacytoid dendritic cells via TLR7 (which recognizes single-stranded RNA) and TLR9 (which recognizes CpG DNA). These plasmacytoid DCs produce massive amounts of **type I interferons (IFN-alpha/beta)**, creating the characteristic "interferon signature" observed in SLE patients. IFN-alpha, in turn, activates dendritic cells, T cells, and B cells, further breaking tolerance.

This innate activation leads to **B cell hyperactivity**, with polyclonal B cell activation producing a diverse array of autoantibodies. The most important include **anti-dsDNA antibodies**, which are highly specific for SLE, and **anti-Smith (anti-Sm) antibodies**. Anti-nuclear antibodies (ANA) are sensitive but not specific for the disease.

The pathological damage in SLE is driven largely by **immune complex deposition**. Autoantibodies combine with nuclear antigens to form immune complexes that deposit in tissues including the glomeruli, skin, joints, and blood vessels. These deposited complexes activate complement, generating C3a and C5a, which recruit inflammatory cells and cause tissue damage through a Type III hypersensitivity mechanism. **Lupus nephritis**, the deposition of immune complexes in the glomeruli leading to complement activation, inflammation, and ultimately renal failure, is a major cause of morbidity. T cell abnormalities, including expanded T follicular helper cells and reduced Treg function, also contribute to disease pathogenesis.

Several key autoantibodies carry clinical significance. Anti-dsDNA correlates with disease activity, especially nephritis. Anti-Sm is highly specific for SLE. Anti-phospholipid antibodies predispose to thrombosis and pregnancy loss in antiphospholipid syndrome. Anti-Ro and anti-La antibodies are associated with neonatal lupus and congenital heart block.

Treatment of SLE is guided by disease severity. Hydroxychloroquine is the standard of care for all patients. Corticosteroids, mycophenolate, and cyclophosphamide (for severe nephritis) provide broader immunosuppression. Newer biologic therapies include belimumab, which targets BAFF, and anifrolumab, which blocks the type I interferon receptor (IFNAR1).

### III. Rheumatoid Arthritis (RA)

Rheumatoid arthritis is a chronic inflammatory arthritis that primarily affects synovial joints, presenting as a symmetric polyarthritis of the small joints. It affects women three times more often than men, with peak onset between ages 40 and 60 years, and has a prevalence of approximately 1%. The strongest genetic association is with HLA-DR4, explained by the shared epitope hypothesis, which proposes that specific amino acid sequences in the HLA-DRB1 peptide-binding groove predispose to RA.

The immunopathogenesis of RA begins with an **initiating event** in which an environmental trigger, such as smoking, periodontal disease caused by Porphyromonas gingivalis, or mucosal dysbiosis, acts on a genetically susceptible individual. A key molecular event is **citrullination**, in which PAD (peptidyl arginine deiminase) enzymes convert arginine residues to citrulline in proteins, generating neo-epitopes that the immune system has not been tolerized against. This gives rise to **anti-citrullinated protein antibodies (ACPA/anti-CCP)**, which are highly specific for RA and can precede symptoms by years. Rheumatoid factor (RF), an IgM directed against the Fc portion of IgG, is less specific and is found in other conditions as well.

The hallmark of RA is **synovial inflammation**. CD4+ Th1 and Th17 cells infiltrate the synovium, producing IFN-gamma and IL-17 respectively. Macrophages produce **TNF-alpha, IL-1, and IL-6**, which are the major drivers of inflammation and tissue destruction. B cells produce RF and ACPA locally, forming immune complexes that activate complement. The inflamed synovium undergoes dramatic transformation through **pannus formation**, in which hyperplastic synovial tissue with granulation tissue invades and destroys cartilage and bone. Osteoclast activation through the RANKL-RANK pathway drives bone erosion, while matrix metalloproteinases degrade the cartilage matrix.

Treatment begins with methotrexate as the anchor disease-modifying antirheumatic drug (DMARD). Biologic therapies target specific inflammatory pathways: **anti-TNF** agents (infliximab, adalimumab, etanercept), anti-IL-6R (tocilizumab), CTLA-4-Ig (abatacept), anti-CD20 (rituximab), and JAK inhibitors (tofacitinib, baricitinib).

<image>A diagram illustrating the immunopathogenesis of rheumatoid arthritis in a synovial joint. The joint cross-section shows normal cartilage and bone on the left side and inflamed, destroyed joint on the right. In the inflamed synovium: CD4+ T cells (Th1 and Th17) are shown producing IFN-gamma and IL-17. Macrophages are shown producing TNF-alpha, IL-1, and IL-6 (highlighted as key cytokines). B cells and plasma cells produce rheumatoid factor (RF) and anti-CCP antibodies, forming immune complexes that deposit in the synovium and activate complement. The pannus (hyperplastic synovial tissue with fibroblast-like synoviocytes) is shown invading cartilage. Osteoclasts at the bone-pannus junction are shown eroding bone (RANKL from T cells and fibroblasts activating RANK on osteoclast precursors). Matrix metalloproteinases (MMPs) from fibroblast-like synoviocytes and macrophages degrade cartilage matrix. An inset shows citrullination: PAD enzyme converting arginine to citrulline in a protein, with the citrullinated peptide being presented on HLA-DR4 to a CD4+ T cell. Therapeutic targets are indicated: anti-TNF, anti-IL-6R, CTLA-4-Ig, anti-CD20.</image>

### IV. Multiple Sclerosis (MS)

Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system, affecting both the brain and spinal cord. It affects women three times more often than men, typically presenting between ages 20 and 40, with prevalence increasing with latitude. The strongest genetic association is with HLA-DRB1*15:01, and additional susceptibility is conferred by polymorphisms in IL-2Ralpha and IL-7Ralpha.

The central pathogenic mechanism involves **autoreactive CD4+ T cells**, primarily of the Th1 and Th17 subsets, directed against myelin antigens including myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG). Disease initiation is thought to occur through molecular mimicry, in which viral antigens such as those from Epstein-Barr virus share epitopes with myelin proteins, or through bystander activation during CNS infection.

The pathogenesis proceeds through a defined series of steps. First, autoreactive T cells are activated in the periphery by cross-reactive or self-antigen. These activated T cells upregulate adhesion molecules, particularly VLA-4 (alpha4-beta1 integrin), which allows them to cross the blood-brain barrier by binding VCAM-1 on endothelial cells. Once within the CNS, T cells encounter myelin antigens presented by local microglia and perivascular macrophages, leading to reactivation. Th1 cells produce IFN-gamma, which activates macrophages that directly destroy myelin. Th17 cells produce IL-17, recruiting neutrophils and causing further disruption of the blood-brain barrier. CD8+ T cells also contribute by directly killing oligodendrocytes through MHC class I-restricted cytotoxicity. B cells and antibodies play additional roles through anti-myelin antibodies that trigger complement-mediated demyelination, and through their function as antigen-presenting cells.

The consequence of this immune attack is demyelination, which impairs nerve conduction and produces neurological deficits. The disease characteristically follows a remitting-relapsing pattern, with episodes of inflammation and demyelination followed by partial remyelination, but progressive axonal loss accumulates over time.

Experimental autoimmune encephalomyelitis (EAE) serves as the animal model for MS, induced by immunization with myelin antigens plus adjuvant, and can be transferred by autoreactive T cells. Treatments include interferon-beta, glatiramer acetate, natalizumab (anti-VLA-4, which blocks T cell entry into the CNS), fingolimod (which sequesters lymphocytes in lymph nodes), ocrelizumab (anti-CD20), and cladribine.

### V. Type 1 Diabetes (T1D)

Type 1 diabetes results from the autoimmune destruction of insulin-producing **pancreatic beta cells** in the islets of Langerhans, leading to insulin deficiency and hyperglycemia. It typically presents in childhood or adolescence, though it can occur at any age, and lacks a strong sex predilection. The highest incidence is found in Finland and Sardinia. Genetic susceptibility is strongly linked to HLA-DR3 and HLA-DR4, with DR3/DR4 heterozygotes carrying the highest risk of approximately 5%. HLA-DQ8, HLA-DQ2, and polymorphisms in CTLA-4, PTPN22, and the insulin gene VNTR also contribute.

The immune attack is directed against several **target antigens** expressed by beta cells, including insulin, glutamic acid decarboxylase (GAD65), insulinoma-associated antigen-2 (IA-2), and zinc transporter 8 (ZnT8). **Autoantibodies** against these antigens, including anti-insulin (IAA), anti-GAD65, anti-IA-2, and anti-ZnT8, appear years before clinical disease and serve as predictive biomarkers. The presence of two or more autoantibodies predicts greater than 80% risk of progression to clinical T1D. However, while autoantibodies are valuable markers, the actual destruction of beta cells is primarily T cell-mediated.

The **T cell-mediated destruction** involves CD4+ Th1 cells specific for beta cell antigens, which produce IFN-gamma and activate macrophages. CD8+ cytotoxic T lymphocytes directly kill beta cells that express target peptides on MHC class I. The histological hallmark is **insulitis**, an inflammatory infiltrate of T cells, macrophages, and B cells within and around the islets. The destructive process is gradual, and clinical diabetes only manifests when approximately 80-90% of beta cells have been destroyed.

Several **environmental triggers** have been implicated. Viral infections, particularly enteroviruses such as Coxsackievirus B and rubella, may initiate autoimmunity through molecular mimicry or bystander activation. Dietary factors, including the debated role of cow's milk proteins and vitamin D deficiency, have been investigated. Reduced gut microbiome diversity has also been associated with increased T1D risk.

Treatment currently relies on insulin replacement, as there is no cure. However, immunotherapy trials have shown promise, with teplizumab (anti-CD3) demonstrating the ability to delay onset in high-risk individuals and receiving FDA approval for stage 2 T1D.

<image>A diagram illustrating the immunopathogenesis of type 1 diabetes. The pancreatic islet of Langerhans is shown at the center, with beta cells (containing insulin granules) being attacked by immune cells. CD8+ CTLs are shown recognizing beta cell antigens (insulin peptide) on MHC class I and killing beta cells via perforin/granzyme pathway. CD4+ Th1 cells are shown producing IFN-gamma, which activates macrophages that produce TNF-alpha and free radicals (NO, ROS), causing additional beta cell death. B cells/plasma cells are shown producing anti-insulin, anti-GAD65, and anti-IA-2 antibodies (noted as biomarkers but not primary mediators of destruction). A timeline below shows the natural history: genetic susceptibility (HLA-DR3/DR4) → environmental trigger → autoimmune activation → progressive beta cell loss (declining beta cell mass curve) → metabolic abnormalities (impaired glucose tolerance) → clinical diabetes when approximately 80-90% of beta cells are destroyed → complete beta cell loss. Autoantibodies (IAA, anti-GAD65, anti-IA-2, anti-ZnT8) are shown appearing during the pre-clinical phase, years before symptom onset.</image>

### VI. Principles of Autoimmune Disease Treatment

The treatment of autoimmune diseases draws on several general strategies. **Immunosuppression** with agents such as corticosteroids, methotrexate, azathioprine, mycophenolate, and cyclophosphamide provides broad dampening of immune responses. **Targeted biologics** offer more specific intervention, including anti-TNF, anti-IL-6, anti-IL-17, anti-CD20, CTLA-4-Ig, and anti-BAFF. **Small molecule inhibitors** such as JAK inhibitors (tofacitinib, baricitinib) block cytokine signaling pathways intracellularly.

More experimental approaches aim for **antigen-specific tolerization**, seeking to restore tolerance without global immunosuppression. These include tolerogenic dendritic cells, peptide-MHC complexes, and regulatory T cell therapy. For severe, refractory disease, **stem cell transplantation** using autologous hematopoietic stem cell transplant can effectively "reset" the immune system.

The fundamental challenge in treating autoimmune disease remains balancing sufficient immune suppression to control disease with the inevitable increase in infection risk, and ultimately achieving disease-specific tolerance without compromising overall immunity.

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