# Appendix C: Glossary

**Anergy**
A state of functional unresponsiveness in T or B lymphocytes induced when an antigen receptor is engaged without adequate costimulatory signals. Anergic cells remain alive but fail to proliferate or produce effector cytokines upon subsequent antigen exposure, serving as a peripheral tolerance mechanism.

**Antigen-Specific Immunotherapy (ASIT)**
A therapeutic approach designed to selectively modulate the immune response to a defined disease-relevant antigen (e.g., an autoantigen or allergen) rather than broadly suppressing immune function. The goal is to restore or induce tolerance to the specific target while preserving protective immunity elsewhere.

**APC (Antigen-Presenting Cell)**
A cell type—including dendritic cells, macrophages, and B cells—that processes protein antigens into peptide fragments and displays them on MHC molecules for recognition by T cells. APCs also provide costimulatory signals that determine whether the resulting T cell response is activating or tolerizing.

**Autoantibody**
An antibody produced by the immune system that erroneously targets one of the host's own proteins or cellular components. Autoantibodies (e.g., anti-GAD65) are frequently used as biomarkers of autoimmune disease activity or risk, though they are not always directly pathogenic.

**Autoantigen**
A self-protein or self-molecule that becomes the target of an inappropriate adaptive immune response in autoimmune disease. Identification of relevant autoantigens (such as insulin or GAD65 in type 1 diabetes) underpins the design of antigen-specific tolerizing therapies.

**C-Peptide**
A byproduct cleaved from proinsulin during insulin biosynthesis, released into circulation in equimolar amounts with endogenous insulin. Serum or urinary C-peptide level is a standard clinical biomarker of residual beta-cell function and is commonly used as an endpoint in type 1 diabetes intervention trials.

**CD3**
A multi-subunit protein complex associated with the T cell receptor (TCR) on the surface of T lymphocytes, essential for transmitting activation signals following antigen recognition. CD3 is the molecular target of therapeutic antibodies such as teplizumab.

**Clonal Deletion**
A central tolerance mechanism occurring primarily in the thymus in which developing T cells (or in the bone marrow for B cells) that react strongly to self-antigens are eliminated via apoptosis. This process removes the most overtly autoreactive lymphocytes before they enter the peripheral circulation.

**Companion Diagnostic**
An assay or device co-developed with a therapeutic to identify patients likely to respond, require dose adjustment, or be at risk of adverse events, often required by regulators as a condition of the drug's approved label. In antigen-specific immunotherapy, companion diagnostics may include autoantibody panels or HLA genotyping tests.

**DSQ (Dysphagia Symptom Questionnaire)**
A validated patient-reported outcome instrument used to quantify the frequency and severity of swallowing difficulty, most notably as a primary or key secondary endpoint in eosinophilic esophagitis clinical trials. Scores are typically derived from daily patient diary entries over a defined recall period.

**EoE (Eosinophilic Esophagitis)**
A chronic, antigen/immune-mediated inflammatory disease of the esophagus characterized by eosinophil-predominant infiltration, often triggered by food antigens, leading to symptoms of dysphagia and, over time, esophageal fibrostenosis. It is a key indication of interest for antigen-specific and food-allergen-targeted therapeutic approaches.

**Epitope**
The specific molecular region of an antigen—typically a short peptide sequence or a conformational surface—that is recognized and bound by a T cell receptor, B cell receptor, or antibody. Epitope specificity determines which immune cells are engaged and is central to designing precisely targeted antigen-specific therapies.

**Epitope Spreading**
A phenomenon in which an immune response initially directed against a single dominant epitope broadens over time to target additional, previously unrecognized epitopes on the same or related antigens. It is implicated in the progressive amplification of autoimmune and allergic responses and is a consideration in the durability of antigen-specific interventions.

**Fibrostenosis**
A pathological process of tissue scarring and narrowing resulting from chronic inflammation, particularly relevant in eosinophilic esophagitis, where persistent eosinophilic inflammation can lead to esophageal strictures requiring dilation. It represents a key long-term disease complication that antigen-specific and anti-inflammatory therapies aim to prevent.

**GAD65 (Glutamic Acid Decarboxylase 65)**
An enzyme expressed in pancreatic beta cells and neurons that is a major autoantigen target in type 1 diabetes. Anti-GAD65 autoantibodies are widely used as a diagnostic and risk-stratification biomarker, and GAD65 itself has been investigated as a tolerizing antigen in therapeutic vaccines.

**Gliadin**
A component protein fraction of gluten found in wheat that contains immunogenic peptide epitopes responsible for triggering the pathological T cell response in celiac disease. Gliadin-derived peptides are a primary target antigen for tolerizing and antigen-specific therapeutic strategies in celiac disease.

**HLA / MHC (Human Leukocyte Antigen / Major Histocompatibility Complex)**
The MHC is the general term for the gene family encoding cell-surface molecules that present peptide antigens to T cells; HLA is the human-specific designation of this system. Specific HLA alleles (e.g., HLA-DQ2/DQ8 in celiac disease) confer differential genetic susceptibility to autoimmune and allergic diseases and are often used to stratify patients for antigen-specific therapy trials.

**Immune Tolerance**
The state in which the immune system does not mount a destructive response against a particular antigen, encompassing central mechanisms (thymic/bone marrow deletion) and peripheral mechanisms (anergy, regulatory T cells, suppression). Restoring lost tolerance to self- or food-antigens is the core therapeutic objective of antigen-specific immunotherapy.

**Nanoparticle (Tolerogenic)**
A synthetic or biodegradable particle engineered to co-deliver a target antigen (and sometimes an immunomodulatory signal) to antigen-presenting cells or lymphoid tissue in a manner that promotes a tolerogenic rather than immunogenic outcome. These platforms are an active area of antigen-specific drug delivery innovation across autoimmune and allergic disease programs.

**pMHC (Peptide-MHC Complex)**
The physical complex formed when a processed antigenic peptide is bound within the groove of an MHC molecule on the cell surface, constituting the actual ligand recognized by a T cell receptor. pMHC complexes are the molecular unit of specificity exploited in engineered antigen-specific therapeutics and diagnostic tetramer assays.

**PFDD (Patient-Focused Drug Development)**
An FDA initiative and regulatory framework for systematically incorporating