Causes And Mechanisms Leading To Autoimmunity
In Hashimoto’s Thyroiditis
Ian Y.H. Chua
1, 2, 3, 4
16 March 2025
Abstract
The aberrant expression of MHC Class II molecules on thyroid follicular cells
(thyrocytes) is a central mechanism in the pathogenesis of Hashimoto’s Thyroiditis.
Thyrocytes do not normally express MHC Class II molecules. They are expressed only on
professional antigen-presenting cells (APCs) like dendritic cells, macrophages, and B
cells. In Hashimoto’s Thyroiditis, thyroid follicular cells aberrantly express MHC Class II
molecules. This abnormal expression allows thyrocytes to present autoantigens (e.g.,
thyroglobulin and thyroid peroxidase) directly to CD4+ T helper cells, triggering an
autoimmune attack which subsequently leads to the destruction of the thyroid gland.
There are several causes of autoimmunity in Hashimoto’s Thyroiditis. This paper provides
a detailed mechanistic analysis of how genetic factors, environmental triggers, immune
system dysregulation, hormonal inuences, gut microbiome alterations, and stress
contribute to the expression of MHC Class II proteins. Specic biomolecules, signaling
pathways, and transcription factors involved in MHC Class II expression are explored to
provide a comprehensive understanding of these regulatory mechanisms.
1. Genetic Factors and MHC Class II Expression
1.1 CIITA: The Master Regulator of MHC Class II
• The Class II Transactivator (CIITA) is the master regulator of MHC Class II gene
transcription.
• CIITA is induced by IFN-γ via JAK1/2-STAT1 signaling, promoting MHC Class II
expression in antigen-presenting cells (APCs) and non-professional APCs such
as thyroid follicular cells under inammatory conditions.
• Mutations in CIITA, RFX5, RFXANK, or RFXAP impair MHC Class II expression,
leading to Bare Lymphocyte Syndrome (BLS) (Reith & Mach, 2001).
1.2 HLA Polymorphisms and Autoimmunity
• Polymorphisms in HLA-DR, HLA-DQ, and HLA-DP genes modulate antigen
presentation eiciency.
• Certain alleles, such as HLA-DR3 and HLA-DR5, are associated with increased
susceptibility to Hashimoto's thyroiditis by presenting thyroid antigens (TPO,
thyroglobulin) to autoreactive T cells.
2. Environmental Triggers and MHC Class II Upregulation
2.1 Iodine Excess or Deciency
• High iodine intake enhances MHC Class II expression via:
o Increased ROS production by DUOX2/DUOXA2 (NADPH oxidase), leading
to oxidative stress and activation of the NF-κB pathway.
o IFN-γ and TNF-α secretion by inltrating macrophages and dendritic cells.
o Upregulation of CIITA, which increases MHC Class II expression in thyroid
cells (Tomer & Huber, 2009).
• Iodine deciency can indirectly reduce Treg cell function, causing an
inammatory environment favoring MHC Class II expression on thyrocytes.
2.2 Viral and Bacterial Infections
• Viruses such as Epstein-Barr Virus (EBV) and Hepatitis C Virus (HCV) upregulate
MHC Class II expression by:
o Activating TLR3 and TLR7 on APCs, stimulating IRF-1, which enhances
CIITA expression.
o EBV-encoded LMP1 mimics TNF receptor signaling, inducing NF-κB
activation and increasing MHC Class II expression (Mancao &
Hammerschmidt, 2007).
• Bacterial infections such as Yersinia enterocolitica trigger molecular mimicry
against TSH receptor, leading to antigen presentation via MHC Class II.
2.3 Radiation Exposure
• Ionizing radiation induces dsDNA breaks, activating ATM kinase and the p53
pathway, leading to cytokine release (IL-1β, IL-6) and IFN-γ-mediated CIITA
upregulation in damaged cells.
2.4 Chemical and Toxin Exposure
• Bisphenol A (BPA) and heavy metals disrupt immune tolerance by modulating
NF-κB and increasing CIITA expression in APCs.
• Cigarette Smoking and MHC Class II Expression in Hashimoto’s Thyroiditis:
o Activation of TLR4 and NF-κB signaling: Components of cigarette smoke,
such as nicotine and acrolein, activate TLR4 on macrophages and
dendritic cells, leading to NF-κB translocation and the transcription of
pro-inammatory cytokines (Yang et al., 2020).
o Induction of oxidative stress: Smoking increases reactive oxygen species
(ROS), which further activate NF-κB and induce NADPH oxidase (NOX2),
enhancing cytokine production (Bourgeois et al., 2016).
o Macrophage polarization to M1 phenotype: Nicotine exposure shifts
macrophages toward a pro-inammatory (M1) phenotype, which secretes
TNF-α, IL-6, and IFN-γ, all of which contribute to MHC Class II
upregulation by activating CIITA transcription (Arnson et al., 2010).
o Increased PAD4-mediated citrullination: Smoking induces
peptidylarginine deiminase 4 (PAD4), leading to citrullination of self-
proteins, creating neoantigens that are more likely to be presented via
MHC Class II molecules (Makrygiannakis et al., 2008).
o Dendritic cell maturation and antigen presentation: The inammatory
milieu leads to increased dendritic cell activation and antigen
presentation, amplifying MHC Class II expression and immune system
activation.
3. Immune System Dysregulation and MHC Class II
• Defective regulatory T cell (T
reg
) function reduces suppression of autoreactive T
cells, leading to increased IFN-γ production, which enhances MHC Class II
expression.
• Abnormal antigen presentation by thyroid follicular cells occurs when IFN-γ
activates STAT1, promoting CIITA transcription, thus transforming thyroid cells
into antigen-presenting cells.
4. Hormonal Inuences
• Estrogen enhances the PI3K/Akt/mTOR pathway, stabilizing IRF4, increasing
MHC Class II expression.
• Pregnancy temporarily reduces MHC Class II expression, but postpartum
immune reactivation can trigger autoimmunity.
5. Gut Microbiome and "Leaky Gut"
• Dysbiosis-induced LPS (lipopolysaccharide) activation of TLR4 increases IL-6
and IFN-γ, promoting MHC Class II upregulation.
• Increased zonulin levels disrupt gut barrier integrity, leading to systemic
inammation and MHC Class II induction on extralymphoid tissues. Zonulin
modulates the tight junctions between intestinal epithelial cells, controlling
what passes through the gut lining into the bloodstream. Triggers for Zonulin
release include gluten (gliadin) in genetically susceptible individuals (e.g., celiac
disease), bacterial overgrowth or infections (e.g., Enterobacteriaceae), dysbiosis
(microbiome imbalances), or stress and inammation.
6. Stress and Psychological Factors
Chronic stress activates the HPA axis, leading to increased cortisol, which reduces T
reg
function, enhancing IFN-γ-driven MHC Class II expression.
Conclusion
MHC Class II expression is inuenced by a complex interplay of genetic, environmental,
immunological, hormonal, microbial, and psychological factors. The molecular
pathways driving its upregulation include IFN-γ-JAK-STAT1 signaling, NF-κB activation,
oxidative stress, and cytokine-mediated CIITA regulation. Understanding these
mechanisms provides insights into autoimmune pathogenesis and therapeutic
strategies targeting MHC Class II-mediated antigen presentation.
Acknowledgments
This paper was developed with the assistance of ChatGPT 4.0, which provided insights and renements in the
articulation of philosophical and scientic concepts.
1
Founder/CEO, ACE-Learning Systems Pte Ltd.
2
M.Eng. Candidate, Texas Tech University, Lubbock, TX.
3
M.S. (Anatomical Sciences Education) Candidate, University of Florida College of Medicine, Gainesville, FL.
4
M.S. (Medical Physiology) Candidate, Case Western Reserve University School of Medicine, Cleveland, OH.
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