HLA Haplotypes and Neuroinflammatory Profiles in PSP

Overview

Progressive supranuclear palsy (PSP) has traditionally been considered a relatively uniform four-repeat tauopathy. However, emerging evidence from Forrest et al. (2026) demonstrates that HLA (human leukocyte antigen) haplotypes correlate with distinct clinical and immunopathological phenotypes, suggesting that PSP may encompass multiple aetiological-pathogenic events including targetable autoimmune mechanisms ^{1Distinct neuroinflammatory profiles in progressive supranuclear palsy associated with HLA haplotypes2026 · Brain Communications · DOI 10.1093/braincomms/fcag084 · PMID 41884598Open reference}. This finding has profound implications for patient stratification in disease-modifying therapy trials.

HLA molecules are critical for antigen presentation to T cells and regulate immune responses. Prior studies identified rare HLA haplotypes in PSP, but the functional consequences of these associations remained unknown ^{2HLA haplotypes in progressive supranuclear palsy2017 · Neurology · PMID 28642332Open reference}. The 2026 study bridges this gap by combining neuropathological analysis with machine learning to demonstrate that HLA-defined groups show distinct neuroinflammatory profiles and symptom progression sequences.

HLA Biology and Neurodegeneration

HLA Class I and Class II Molecules

HLA genes encode major histocompatibility complex (MHC) molecules that present peptide antigens to T-cell receptors:

• HLA class I (HLA-A, -B, -C): Presents endogenous peptides to CD8+ cytotoxic T cells

• HLA class II (HLA-DR, -DP, -DQ): Presents exogenous peptides to CD4+ helper T cells

In the CNS, microglial cells express both HLA class I and class II molecules, enabling them to present antigens and interact with T cells. This capacity is enhanced in neurodegenerative conditions where inflammatory responses are activated.

HLA in PSP: Prior Knowledge

Prior to the 2026 study, HLA associations with PSP included:

• DRB115:01-DQB106:02: A haplotype linked to narcolepsy, previously associated with PSP

• Class I HLA associations: Found in genome-wide association studies of PSP

• Frequency: HLA associations in PSP are rarer and less pronounced than in Alzheimer’s disease

The Forrest et al. (2026) study expanded on these findings by investigating functional consequences rather than merely genetic associations.

Study Design and Methods

Cohort and Tissue Analysis

Forrest et al. (2026) analyzed 32 PSP cases with known HLA haplotypes ^{1Distinct neuroinflammatory profiles in progressive supranuclear palsy associated with HLA haplotypes2026 · Brain Communications · DOI 10.1093/braincomms/fcag084 · PMID 41884598Open reference}:

• Clinical data: Retrospective collection of symptom onset, progression, and clinical scores

• Neuropathological analysis: Evaluation of T cells, B cells, microglia, and phosphorylated-tau (p-Tau) cytopathologies

• Brain regions analyzed: Basal ganglia, brainstem, and cortical regions

• Immunohistochemistry: Staining for CD8+ T cells, CD20+ B cells, IBA1+ microglia, and p-Tau (AT8)

Machine Learning Analysis

The study applied machine learning to identify patterns invisible to conventional statistical methods:

1. Pathological variable ratios: Ratios of different immune cell types and inflammatory markers

2. Symptom progression sequences: Order of clinical symptom onset

3. HLA-group classification: Classification of cases by HLA haplotype

The machine learning models revealed that specific ratios of neuroinflammatory markers reliably distinguished HLA haplotypes, exceeding the performance of individual biomarkers alone.

Key Findings

1. Regional Differences in Neuroinflammatory Severity

Between HLA-defined groups, neuropathological analysis revealed significant regional differences:

Brain Region	Key Finding
Basal ganglia	Differential microglia load by HLA haplotype
Subthalamic nucleus	Varying p-Tau burden across HLA groups
Frontal cortex	Different cytotoxic T cell density
Brainstem	Variable astrocyte activation patterns

2. Specific Neuroinflammatory Ratios Distinguish HLA Haplotypes

Machine learning identified that the ratio of neuroinflammatory markers (not absolute values) most reliably distinguished HLA haplotypes. Key discriminators included:

• Microglia-to-lymphocyte ratio: Different across HLA-defined groups

• CD8+ T cell to B cell ratio: HLA-associated patterns

• p-Tau to microglia density ratio: Reflects differential immune response to tau pathology

• Cytokine milieu ratios: Balance of pro-inflammatory vs regulatory markers

These ratios suggest that HLA haplotypes influence the type and balance of immune response rather than simply its intensity.

3. Symptom Progression Sequences Vary by HLA Haplotype

Perhaps the most clinically relevant finding: symptom progression sequences differed by HLA haplotype. This indicates that:

• The order of clinical symptom appearance is influenced by HLA-defined immune profile

• Patients with different HLA haplotypes may present with subtly different clinical phenotypes

• This could explain some of the phenotypic heterogeneity within PSP

• Implications for clinical trial patient stratification and treatment targeting

4. HLA Haplotype-Dependent Autoimmune Mechanisms

The study supports the notion that PSP pathology may be associated with various aetiological-pathogenic events, including rareyly occurring targetable autoimmune mechanisms. This expands the conceptual framework of PSP beyond pure tauopathy to include an immune-mediated component in some cases.

Clinical and Therapeutic Implications

Patient Stratification for Clinical Trials

The HLA-dependent neuroinflammatory profiles have direct implications for disease-modifying therapy trials:

• HLA-stratified enrichment: Trials could enrich for patients with specific immune profiles most likely to respond to immunomodulatory therapies

• Precision medicine approach: Different HLA groups may respond differently to the same treatment

• Biomarker-driven selection: Neuroinflammatory ratios could serve as stratification biomarkers

Immunomodulatory Therapeutic Approaches

The findings support exploration of immunomodulatory strategies in PSP:

Approach	Rationale	Target Population
HLA-targeted immunotherapy	Antigen presentation dysregulation	HLA-risk haplotype carriers
T cell modulation	Cytotoxic T cell involvement	High CD8+ density groups
B cell-targeted therapy	B cell participation	DRB115:01-DQB106.02 carriers
Microglial modulation	HLA-dependent microglial profiles	Specific ratio-based groups

Comparison with Alzheimer’s Disease HLA Findings

HLA associations in PSP differ from those in Alzheimer’s disease:

Feature	PSP (Forrest 2026)	AD
HLA association strength	Moderate, specific	Strong, widespread
Primary immune cell type	Mixed (T, B, microglia)	Microglia-dominated
TREM2 interaction	Weaker	Stronger
HLA-risk haplotype effect	Phenotype-modifying	Risk-modifying
Autoimmune component	Present in subset	Minimal

Mechanistic Framework

Proposed HLA-Immune-Tau Interaction Model

HLA Haplotype Variants
         |
         v
Differential Antigen Presentation Capacity
         |
         +---> CD8+ T Cell Activation ---> Cytotoxic T Cell Infiltration
         |
         +---> Microglial HLA Expression ---> Altered Phagocytosis
         |
         +---> Cytokine Profile ---> Neuroinflammatory Balance
         |
         v
Distinct Neuroinflammatory Phenotype
         |
         v
Symptom Progression Sequence Differences
         |
         v
Clinical Heterogeneity within PSP

Why HLA Haplotypes Matter in PSP

Several non-mutually exclusive mechanisms may explain the HLA-PSP relationship:

1. Antigen presentation of tau peptides: HLA molecules may present specific tau epitopes, triggering T-cell responses

2. Microglial antigen processing: Different HLA haplotypes affect how microglia process and present tau-derived antigens

3. Molecular mimicry: Cross-reactivity between infectious agents and brain antigens presented by specific HLA molecules

4. Regulatory T-cell dysfunction: HLA-linked differences in regulatory immune responses

5. B-cell collaboration: HLA class II molecules on B cells may present tau antigens to CD4+ T cells

Research Directions

Emerging Questions

The 2026 study opens several research avenues:

• Functional validation: Which specific HLA alleles drive the neuroinflammatory differences?

• Longitudinal studies: Do HLA-defined groups show different disease progression rates?

• Treatment response: Do HLA-targeted immunotherapies show differential efficacy by haplotype?

• Mechanism dissection: What tau peptides are presented by risk HLA molecules?

• Broader tauopathy applicability: Do similar HLA-dependent patterns exist in CBD, FTD, and other 4R tauopathies?

Integration with Single-Cell Studies

The findings complement single-cell microglial profiling studies ^{3Single-cell microglial profiling in PSP2024 · Nature · DOI 10.1038/s41586-024-07890-5Open reference}:

• Single-cell studies reveal microglial heterogeneity in PSP

• HLA haplotype may determine which microglial subpopulations predominate

• Combined analysis could identify HLA-driven microglial transcriptional signatures

CSF and Blood Biomarker Correlates

Work is needed to identify peripheral correlates of HLA-dependent neuroinflammatory profiles:

• CSF cytokine/chemokine panels differentiating HLA groups

• Blood immune cell phenotyping by HLA haplotype

• Plasma/serum biomarkers reflecting CNS immune states

Cross-References

• Neuroinflammation in PSP — broader neuroinflammatory context

• PSP Peripheral Immune Dysfunction — peripheral immune cell alterations

• PSP Neuropathology — p-Tau and cellular pathology

• PSP Cognitive Impairment — cognitive profiles by HLA group

• PSP Genetics — genetic background including HLA associations

• 4R-Tauopathy Brain Region Vulnerability — vulnerability patterns