Immune heterogeneity and the immune–barrier–hydrops framework in Ménière’s disease: current evidence, uncertainties, and testable hypotheses

Ménière’s disease presents with episodic vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness, and commonly features endolymphatic hydrops. Yet similar hydropic phenotypes arise in patients with markedly different clinical courses, patterns of bilateral involvement, and treatment responses, suggesting that more than one upstream process may lead to hydrops. Human tissue studies, peripheral immune profiling, allergy- and autoimmunity-associated findings, and blood–labyrinth barrier imaging all point to possible immune contributions in some patients. Their interpretation remains constrained by selected tissue sources, inconsistent definitions of disease stage, heterogeneous assays, and limited independent replication. We examined four candidate effector mechanisms: innate inflammatory amplification and inflammasome signaling; type 2 immunity and mast-cell-mediated modulation of vascular or fluid homeostasis; antibody-, immune-complex-, or complement-mediated injury; and antigen-specific cytotoxic T-cell injury. We distinguished direct observations from the human inner ear from peripheral and imaging associations, experimental perturbations, and mechanistic inference. We then evaluated these evidence streams against four competing causal structures: immune-first, hydrops- or tissue-stress-first, common-upstream-factor, and nonimmune hydropic models. In this framework, the blood–labyrinth barrier is not assumed to be an obligatory step between immune activation and hydrops. Its biological state may instead act as a mediator, effect modifier, common consequence, or component of nonimmune microvascular disease, depending on the causal structure under consideration. MRI enhancement, in turn, remains an imperfect and protocol-dependent proxy for that state. Current evidence does not distinguish these models reliably at the individual-patient level or support stable immune endotypes for treatment selection. It does, however, make two stronger claims difficult to sustain: that MD follows a universal immune-first sequence and that immune activity is required for hydropic progression in every patient. The framework is therefore most useful for separating immune detection, mechanistic contribution, and causal initiation, while specifying which observations would discriminate among competing models. Resolving those models will require longitudinal cohorts that align clinical events with repeated immune and standardized imaging measurements, complemented where feasible by local human samples and pathway-specific perturbation.