Why Women Face Greater Risk
The mystery of why women's immune systems turn against their own brains
For decades, the medical community has observed a puzzling pattern: disorders where the immune system mistakenly attacks the central nervous system—such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and autoimmune encephalitis—strike women far more often than men. This stark disparity represents one of the most pronounced sex biases in all of medicine, yet its underlying causes have remained elusive. Today, revolutionary research is unraveling this mystery, revealing complex interactions between sex hormones, genetics, and environmental factors that shape our immune responses in profoundly different ways based on biological sex.
"Stronger adaptive immune responses in females can be observed in different mammals, resulting in better control of infections compared to males. However, this presumably evolutionary difference likely also drives higher incidence of autoimmune diseases" 8 .
Autoimmune disorders of the central nervous system (CNS) occur when the body's defensive machinery mistakenly identifies components of the brain or spinal cord as foreign invaders. This leads to inflammation and tissue damage that can cause a wide range of neurological symptoms, from vision problems and muscle weakness to cognitive impairment and seizures.
Sex hormones—particularly estrogen—play a pivotal role in shaping immune responses. Estrogen receptors are found on various immune cells, including mast cells, macrophages, dendritic cells, T cells, and B cells 1 . These hormones exert complex effects on the immune system:
Estrogen promotes B cell activation, survival, and antibody production, leading to higher antibody responses in females 1 . This enhanced response benefits infection control but increases autoimmune risk.
Estrogen decreases expression of the AIRE gene, a critical transcription factor that helps prevent self-reactivity by promoting tolerance to the body's own tissues 1 .
The concentration of estrogen matters significantly. Low doses tend to promote Th1-type immune responses, while high concentrations favor Th2-type responses 1 .
Beyond hormones, the very genetic blueprint of women predisposes them to autoimmunity:
Females possess two X chromosomes, and to prevent overexpression of X-linked genes, one chromosome is randomly inactivated in each cell. However, approximately 15-23% of genes escape this inactivation, resulting in double the expression of certain immune-related genes 1 .
The X chromosome carries numerous microRNAs that regulate immune function. The doubled expression of these regulatory molecules in females significantly alters their immune response landscape 3 .
Environmental factors—including infections, gut microbiota composition, environmental chemicals, and lifestyle factors such as diet and smoking—further modulate immune function in a sex-dependent manner 3 . The interaction between these external factors and intrinsic biological differences creates a perfect storm for autoimmune development in susceptible women.
In 2021, researchers at the National Eye Institute made a breakthrough discovery that could transform how we treat autoimmune diseases: a unique population of IL-27-producing regulatory B cells (i27-Bregs) that actively suppress inflammation in the central nervous system 2 .
The research team, led by Dr. Charles Egwuagu, employed a multi-faceted approach to isolate and characterize these previously unknown cells 2 :
Using various assays, the team first demonstrated the existence of IL-27-producing B cells in the peritoneal cavity of mice.
Through careful analysis, they determined these cells originate from the B-1a cell lineage—a subset of innate-like B cells.
When encountering immune stimuli, these specialized B cells stop producing natural IgM antibodies and instead differentiate into IL-27-producing cells that migrate from the peritoneal cavity to secondary lymphoid tissues like the spleen.
The team then purified these i27-Bregs and tested their therapeutic potential in mouse models of two autoimmune conditions: autoimmune uveitis and a multiple sclerosis-like disease.
The findings were striking. Infusions of purified i27-Bregs significantly reduced symptoms in both disease models. The treatment worked through several mechanisms 2 :
(Lag3, PD-1) on immune cells
(Th17/Th1)
into regulatory cells that secrete anti-inflammatory molecules
Perhaps most promisingly, the i27-Bregs demonstrated exceptional therapeutic advantages: they proliferated after injection, sustained IL-27 secretion in central nervous system and lymphoid tissues, and were neither antigen-specific nor disease-specific—suggesting potential applicability across a wide spectrum of autoimmune conditions 2 .
| Characteristic | Description | Significance |
|---|---|---|
| Origin | B-1a cell lineage | Represents an innate-like B cell pathway |
| Key Secretion | Interleukin-27 (IL-27) | Potent anti-inflammatory cytokine |
| Therapeutic Advantage | Proliferate after injection | Longer-lasting effects compared to other Bregs |
| Mechanism | Upregulate inhibitory receptors | Calms overactive immune responses |
| Scope | Not disease-specific | Potential broad applicability across autoimmune conditions |
Understanding sex differences in CNS autoimmunity requires sophisticated experimental approaches. Scientists employ several powerful techniques to unravel these complex interactions:
| Research Tool | Function | Application in Autoimmunity Research |
|---|---|---|
| Four Core Genotype (FCG) Mice | Decouples chromosomal sex from gonadal sex | Isolates effects of XX vs XY chromosomes independent of hormones |
| Bone Marrow Chimeras | Transplantation of bone marrow between sex-matched or mismatched recipients | Determines hematopoietic vs non-hematopoietic contributions to sex differences |
| Single-Cell RNA Sequencing | Measures gene expression in individual cells | Identifies sex-specific immune cell populations and states |
| Hormonal Manipulation | Gonadectomy (ovariectomy/orchiectomy) with hormone replacement | Clarifies specific roles of estrogen, testosterone, and progesterone |
| Cytokine Profiling | Measures levels of immune signaling molecules | Reveals sex differences in inflammatory and anti-inflammatory pathways |
These tools have revealed that sex differences in autoimmunity arise from complex interactions between multiple systems—not just hormones or genetics alone. For instance, studies using FCG mice have shown that both chromosomal and gonadal sex contribute independently to immune differences 3 .
The growing understanding of sex differences in CNS autoimmunity is paving the way for more personalized therapeutic approaches. Current research focuses on:
Systematically studying treatment responses in males versus females to identify divergent therapeutic efficacy and side effects 8 .
Exploring innovative treatments like i27-Breg cell infusions or exosomes containing anti-inflammatory cytokines that could provide longer-lasting relief with fewer side effects 2 .
Investigating how hormone levels or receptor activity might be optimized to reduce autoimmune activity without compromising protective immune function.
As research continues to unravel the intricate dance between our immune systems and our sex biology, one thing becomes increasingly clear: the future of autoimmune treatment lies in approaches specifically tailored to an individual's biological makeup. Understanding why women's immune systems are more prone to turning against their own brains may not only lead to better treatments for autoimmune disorders but also reveal fundamental truths about human immunity that benefit all people, regardless of sex.