Autoimmune Diseases Beyond the Thyroid:

Molecular Mechanisms and Surface Antigen Presentation

Ian Y.H. Chua

1, 2, 3, 4

16 March 2025

Abstract

Autoimmune diseases arise when the immune system erroneously targets the body's

own tissues, often due to aberrant antigen presentation. While thyroid-specic

autoimmune disorders like Hashimoto's thyroiditis and Graves' disease are well-

documented, numerous other organs and tissues are susceptible to similar autoimmune

mechanisms. This paper explores autoimmune diseases aecting the skin,

gastrointestinal system, lungs, cardiovascular system, kidneys, nervous system,

endocrine system, musculoskeletal system, and liver, emphasizing the primary

molecules involved in antigen presentation and their roles in disease progression.

1. Introduction

Autoimmune diseases are characterized by the immune system's failure to distinguish

self from non-self, resulting in chronic inammation and tissue destruction. A key

pathological feature in many autoimmune disorders is the abnormal expression of MHC

Class I and II molecules on non-immune cells, leading to inappropriate antigen

presentation and sustained immune activation. While MHC Class II molecules are

typically restricted to professional antigen-presenting cells (APCs) such as dendritic

cells, macrophages, and B cells, inammatory stimuli such as interferon-gamma (IFN-γ)

can induce their expression in non-immune cells, contributing to autoimmunity.

Similarly, upregulation of MHC Class I molecules and the presentation of cryptic self-

antigens can drive cytotoxic CD8+ T cell responses. This review focuses on non-thyroid

autoimmune diseases, detailing the molecular mechanisms driving antigen presentation

in dierent organs.

2. Autoimmune Diseases in the Skin

2.1 Psoriasis

• Aected Cells: Keratinocytes

• Primary Surface Molecule: Upregulated MHC Class I and II molecules on

keratinocytes

• Mechanism: Chronic inammatory signaling, primarily driven by IL-17 and IL-23-

mediated Th17 responses, leads to inappropriate expression of MHC Class I and

II molecules, exacerbating T cell-mediated skin damage (Lowes et al., 2014).

2.2 Vitiligo

• Aected Cells: Melanocytes

• Primary Surface Molecule: MHC Class I molecules on melanocytes

• Mechanism: IFN-γ and CXCL10 signaling recruit autoreactive CD8+ T cells,

promoting melanocyte destruction via MHC Class I-mediated antigen

presentation (Harris, 2017).

2.3 Pemphigus Vulgaris

• Aected Cells: Keratinocytes

• Primary Surface Molecule: Desmoglein autoantigens on keratinocytes

• Mechanism: Autoantibodies targeting desmogleins disrupt cell-cell adhesion,

leading to acantholysis and blister formation (Amagai, 2015).

3. Autoimmune Diseases in the Gastrointestinal System

3.1 Celiac Disease

• Aected Cells: Enterocytes

• Primary Surface Molecule: MHC Class II molecules (HLA-DQ2/DQ8) on

enterocytes

• Mechanism: Gluten peptides bind to HLA-DQ2/DQ8 molecules, leading to

excessive CD4+ T cell activation and subsequent enterocyte destruction (Abadie

et al., 2011).

3.2 Inammatory Bowel Disease (Crohn’s Disease, Ulcerative Colitis)

• Aected Cells: Colonic epithelial cells

• Primary Surface Molecule: Upregulated MHC Class II molecules on colonic

epithelial cells

• Mechanism: Dysbiosis and chronic inammation induce MHC Class II

expression, enhancing antigen presentation and T cell-driven inammation

(Neurath, 2014).

3.3 Autoimmune Gastritis

• Aected Cells: Gastric parietal cells

• Primary Surface Molecule: MHC Class II molecules on parietal cells

• Mechanism: Autoimmune targeting of the H+/K+ ATPase enzyme disrupts

gastric acid secretion, leading to chronic gastritis (Negrini et al., 2017).

4. Autoimmune Diseases in the Lungs

4.1 Goodpasture Syndrome

• Aected Cells: Alveolar epithelial cells

• Primary Surface Molecule: Collagen IV autoantigens on the alveolar basement

membrane

• Mechanism: Autoantibody binding triggers complement activation, resulting in

lung hemorrhage (Hudson et al., 2003).

4.2 Sarcoidosis

• Aected Cells: Alveolar macrophages

• Primary Surface Molecule: MHC Class II molecules on macrophages

• Mechanism: Persistent antigen stimulation leads to granuloma formation and

chronic lung inammation (Chen et al., 2019).

5. Autoimmune Heart Diseases

5.1 Myocarditis (Autoimmune Cardiomyopathy)

• Aected Cells: Cardiomyocytes

• Primary Surface Molecule: Upregulated MHC Class I molecules on

cardiomyocytes

• Mechanism: Viral infections trigger CD8+ T cell-mediated destruction of

cardiomyocytes (Fairweather et al., 2012).

5.2 Rheumatic Heart Disease

• Aected Cells: Valvular endothelial cells

• Primary Surface Molecule: Molecular mimicry between Streptococcal M

protein and cardiac proteins

• Mechanism: Cross-reactivity leads to immune-mediated heart valve damage

(Carapetis et al., 2016).

6. Autoimmune Neurological Disorders

6.1 Guillain-Barré Syndrome

• Aected Cells: Schwann cells

• Primary Surface Molecule: Ganglioside autoantigens

• Mechanism: Molecular mimicry results in CD8+ T cell-mediated demyelination

(Lehmann et al., 2019).

6.2 Autoimmune Encephalitis (NMDA Receptor Encephalitis)

• Aected Cells: Neurons

• Primary Surface Molecule: NMDA receptor autoantibodies

• Mechanism: Autoantibody binding disrupts neurotransmission, leading to

neuropsychiatric symptoms (Dalmau et al., 2011).

6.3 Sti Person Syndrome

• Aected Cells: GABAergic neurons

• Primary Surface Molecule: GAD65 autoantigen

• Mechanism: T cell-mediated destruction of GABAergic neurons results in

progressive muscle stiness (Meinck et al., 2001).

6.4 Multiple Sclerosis (MS)

• Aected Cells: Oligodendrocytes and neurons

• Primary Surface Molecule: MHC Class II on microglia and astrocytes

• Mechanism: Aberrant MHC Class II expression on microglia leads to excessive

antigen presentation and chronic T cell-mediated demyelination (Wekerle, 2018).

6.5 Neuromyelitis Optica (NMO)

• Aected Cells: Astrocytes

• Primary Surface Molecule: Aquaporin-4 autoantibodies

• Mechanism: Autoantibodies target aquaporin-4, leading to complement

activation and astrocyte destruction (Lennon et al., 2005).

7. Autoimmune Diseases of the Endocrine System (Beyond Thyroid)

7.1 Type 1 Diabetes Mellitus (T1DM)

• Aected Cells: Pancreatic beta cells

• Primary Surface Molecule: MHC Class I and aberrant MHC Class II

expression on beta cells

• Mechanism: Chronic exposure to IFN-γ induces MHC Class II expression,

making beta cells susceptible to CD4+ T cell-mediated destruction (Richardson

et al., 2016).

7.2 Addison’s Disease

• Aected Cells: Adrenal cortical cells

• Primary Surface Molecule: Autoantibodies targeting 21-hydroxylase

• Mechanism: Destruction of adrenal cortex leads to cortisol and aldosterone

deciency (Husebye et al., 2014).

8. Autoimmune Diseases in the Musculoskeletal System

8.1 Rheumatoid Arthritis (RA)

• Aected Cells: Synovial broblasts

• Primary Surface Molecule: MHC Class II on synovial broblasts

• Mechanism: Aberrant MHC Class II expression and CD80/CD86 costimulatory

molecule expression result in persistent synovial inammation (Robinson &

Lindstrom, 2017).

8.2 Polymyositis/Dermatomyositis

• Aected Cells: Skeletal muscle bers

• Primary Surface Molecule: MHC Class I on muscle cells

• Mechanism: Upregulated MHC Class I expression leads to CD8+ T cell-

mediated muscle ber destruction (Dalakas, 2015).

9. Autoimmune Diseases in the Liver

9.1 Autoimmune Hepatitis (AIH)

• Aected Cells: Hepatocytes

• Primary Surface Molecule: MHC Class II on hepatocytes

• Mechanism: Chronic IFN-γ exposure induces MHC Class II expression,

triggering CD4+ T cell-mediated hepatocyte destruction (Manns et al., 2015).

9.2 Primary Biliary Cholangitis (PBC)

• Aected Cells: Biliary epithelial cells

• Primary Surface Molecule: Autoantibodies targeting mitochondrial proteins

• Mechanism: Chronic immune-mediated destruction of biliary ducts leads to

cholestasis and liver brosis (Gershwin & Mackay, 2018).

Conclusion

Autoimmune diseases result from aberrant antigen presentation and immune

dysregulation in non-immune cells. Across dierent organ systems, the inappropriate

expression of MHC Class I or II molecules, autoantigen exposure, and costimulatory

molecule expression contribute to tissue-specic immune attacks. Understanding

these molecular mechanisms is crucial for developing targeted immunotherapies.

Acknowledgments

This paper was developed with the assistance of ChatGPT 4.0, which provided insights and renements in the

articulation of philosophical and scientic concepts.

Founder/CEO, ACE-Learning Systems Pte Ltd.

M.Eng. Candidate, Texas Tech University, Lubbock, TX.

M.S. (Anatomical Sciences Education) Candidate, University of Florida College of Medicine, Gainesville, FL.

M.S. (Medical Physiology) Candidate, Case Western Reserve University School of Medicine, Cleveland, OH.

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