Langerhans cell

**Normal function:** Langerhans cells (LCs) are the resident dendritic cells of the epidermis (mainly stratum spinosum) and other stratified squamous epithelia (oral mucosa, vagina, esophagus). They capture antigen in the skin, migrate via afferent lymphatics to regional lymph nodes (paracortex), and present antigen on MHC II (and cross-present on MHC I) to naïve T cells, bridging innate and adaptive immunity. They are key in type IV (delayed-type) hypersensitivity, such as allergic contact dermatitis (e.g., poison ivy, nickel), where they present haptens-modified self-proteins to T cells during the sensitization phase.

**Origin and markers:** Derive from embryonic precursors (yolk sac/fetal liver) with replenishment from bone marrow–derived monocytes during inflammation. Markers: CD1a, langerin (CD207), S-100, MHC class II. They are not reliably stained by CD68 to the degree macrophages are, and are negative for factor XIIIa (distinguishing them from dermal dendrocytes).

**Birbeck granules:** Rod- or "tennis racket"–shaped cytoplasmic organelles seen on electron microscopy; they are formed by langerin-mediated membrane superimposition and are involved in receptor-mediated endocytosis. They are the classic buzzword for LCs and LCH.

**Langerhans cell histiocytosis (LCH):** Clonal neoplastic proliferation of LCs, driven largely by activating MAPK pathway mutations (BRAF V600E in ~50-60%; also MAP2K1). Seen mostly in children. Histology: large cells with abundant pink cytoplasm and grooved ("coffee bean"/folded) reniform nuclei, with eosinophils in the infiltrate. Cells are S-100+, CD1a+, CD207+ with Birbeck granules on EM. Clinical spectrum: - Eosinophilic granuloma (unifocal or multifocal): lytic bone lesions (skull, ribs, femur) with pain or pathologic fractures; may involve lung (smokers, young adults). - Hand-Schüller-Christian disease: triad of calvarial lytic lesions, diabetes insipidus, and exophthalmos; typically in young children. - Letterer-Siwe disease: acute disseminated form in infants (<2 years) with skin rash (seborrheic/eczematous), hepatosplenomegaly, lymphadenopathy, pancytopenia, and bone lesions; worst prognosis. - Treatment: observation or curettage for localized disease; vinblastine plus prednisone for multisystem disease; BRAF inhibitors (e.g., vemurafenib) for refractory BRAF V600E disease.

**High-yield distinctions:** LCs vs. melanocytes (neural crest, stratum basale, make melanin, S-100+) vs. Merkel cells (neuroendocrine, mechanoreceptors, stratum basale, CK20+ and associated with Merkel cell carcinoma). LCs are in the stratum spinosum, are immune cells, and are CD1a+.

**Associations:** LCs are also involved in HIV (can be early targets via CD4 and langerin, though langerin can also help degrade virions), and in graft-versus-host disease and skin graft rejection (donor-derived antigen-presenting cells).