What is Immune Privilege?
Immune privilege is an active biological mechanism that protects vital organs with limited regenerative capacity from inflammatory immune responses that could otherwise cause irreversible functional damage. 1, 2
Core Concept
Immune privilege represents a sophisticated network of immunoregulatory processes rather than simple physical isolation. 2 The concept has evolved from the outdated notion of "antigen sequestration behind barriers" to recognition of active immunosuppressive mechanisms that maintain organ function while preventing potentially damaging immune reactions. 3, 4
Anatomical Sites with Immune Privilege
Classical immune-privileged sites include:
- The eye (anterior chamber, vitreous, retina) - lacks lymphatic drainage and actively suppresses immune responses to prevent vision-threatening inflammation 1, 3
- The brain and central nervous system - where inflammation disrupts critical neural architecture 1, 2
- The testes and reproductive organs - constitutively express FasL to eliminate invading lymphocytes 3
- The pregnant uterus/placenta - protects the semi-allogeneic fetus from maternal immune rejection 2, 5
Additional sites with relative immune privilege:
- Heart valves - demonstrate protection from alloimmune injury during transplantation 5
- Hair follicles - an underappreciated but clinically important immune-privileged site 2
- Articular cartilage 5
- Certain transplant sites in experimental models (anterior eye chamber, bone marrow) 1
Mechanisms of Immune Privilege
Active immunosuppressive mechanisms include:
- FasL expression - constitutive expression in privileged tissues (eye, testes) kills invading Fas-expressing lymphocytes through apoptosis 3
- Absence of lymphatic drainage - the eye lacks a lymphatic system, preventing antigen presentation to the systemic immune system 1
- Specialized microenvironments - create local immunosuppressive conditions through cytokine profiles and cellular interactions 1, 2
- Physical barriers - blood-tissue barriers (blood-brain barrier, blood-retinal barrier) limit immune cell access, though this is now understood as only one component rather than the sole mechanism 2, 4
Clinical Significance
The concept has direct therapeutic implications:
- Corneal transplantation and meniscal transplantation can be performed without systemic immunosuppression due to immune privilege 5
- Primary CNS lymphomas are classified as "Large B-cell lymphomas of immune-privileged sites" by the WHO, reflecting their unique biology 1
- Islet transplantation research utilizes immune-privileged sites (anterior eye chamber) in experimental models, though translation to humans faces challenges 1
Loss of Immune Privilege
Breaking the barriers that maintain immune privilege has serious consequences:
- In the eye, any breach (penetrating injury, surgery) risks sympathetic ophthalmia - a sight-threatening autoimmune pan-uveitis where the immune system recognizes both eyes as foreign after exposure to previously sequestered ocular antigens 1
- Intraocular antigens were never presented to the developing immune system as "self," so barrier disruption allows immune surveillance of autoantigens 1
- Psychosocial stress and inflammation can collapse immune privilege in sites like hair follicles, potentially triggering autoimmune conditions 2
Evolutionary Perspective
Immune privilege represents an evolutionary adaptation that enables vulnerable tissues to maintain immune protection without suffering immunopathogenic damage. 4 These tissues share common features: vital function for survival, limited regenerative capacity, and requirement for precise microanatomic structure that inflammation would disrupt. 2, 4, 5