chimerism

**Definition:** An organism containing cells from ≥2 genetically distinct zygotes. Contrast with **mosaicism**, in which genetically different cell lines arise from a SINGLE zygote through postzygotic mutation or nondisjunction (e.g., mosaic Turner 45,X/46,XX; McCune-Albright; Down syndrome mosaicism).

**Types / mechanisms:** 1. **Tetragametic (true) chimerism:** Fusion of two fertilized zygotes (or fertilization of an egg and its polar body by two sperm) early in embryogenesis -> a single embryo with two cell lines. Can produce 46,XX/46,XY chimeras with ambiguous genitalia, true hermaphroditism (ovotesticular DSD), or mixed blood types (e.g., two ABO groups). Often detected incidentally, e.g., during infertility workup or blood typing. 2. **Blood (twin) chimerism:** Dizygotic twins sharing a placental vascular anastomosis (dichorionic or monochorionic placentas with fused vessels) exchange hematopoietic stem cells in utero -> each twin has a mixture of blood cell lines and is immunologically tolerant of the other's cells. Classic in cattle (freemartin). 3. **Microchimerism:** Small numbers of foreign cells persist in an individual. - **Fetomaternal:** Fetal cells persist in the mother for decades after pregnancy (e.g., male DNA in women who have had sons). Hypothesized links to autoimmune disease (systemic sclerosis, SLE, autoimmune thyroid disease) and to tissue repair. - **Maternofetal:** Maternal cells in the fetus. - **Transfusion-associated microchimerism:** After trauma transfusions. 4. **Iatrogenic (artificial) chimerism:** - **Allogeneic hematopoietic stem cell transplant (HSCT):** The recipient becomes a hematopoietic chimera. **Full donor chimerism** = nearly all hematopoietic cells are donor derived; **mixed chimerism** = coexistence of donor and recipient cells. Chimerism is monitored by STR (short tandem repeat) analysis or, in sex-mismatched transplants, by FISH for X/Y. Falling donor chimerism may predict relapse or graft failure. - **Solid organ transplantation:** Passenger leukocytes from the donor organ lead to microchimerism, which may contribute to tolerance. - **Blood transfusion:** Transient microchimerism. In immunocompromised patients, can cause transfusion-associated GVHD.

**Clinical significance / high-yield associations:** - **Immune tolerance:** Chimeras (e.g., dizygotic twins with shared circulation) accept each other's grafts without rejection because of central tolerance (thymic deletion of cells reactive to both cell lines). Basis of the experimental work of Medawar (Nobel Prize 1960) on acquired immunologic tolerance. - **GVHD:** Donor T cells in a chimeric recipient attack host tissues (skin, liver, GI tract). Acute (<100 days; rash, jaundice/elevated bilirubin, diarrhea) vs chronic (scleroderma-like features). - **Blood typing discrepancy:** A "dual population" or mixed-field agglutination on ABO typing suggests chimerism (after transplant, transfusion, or tetragametic). - **Forensics/paternity:** DNA from blood may not match DNA from other tissues (e.g., hair, buccal cells, or sperm), which can cause apparent maternity/paternity exclusion. - **Ovotesticular DSD:** 46,XX/46,XY chimerism is one (uncommon) cause. Most ovotesticular DSD cases are 46,XX with SRY translocation. - **Lab clue:** Karyotype of blood may show two cell lines (46,XX and 46,XY).

**Chimerism vs mosaicism vs heteroplasmy:** - Chimerism: 2+ zygotes, different genomes. - Mosaicism: 1 zygote, postzygotic change, different genotypes in somatic or germline cells. - Heteroplasmy: Mixed normal and mutant mitochondrial DNA in a cell (mitochondrial inheritance).

**Board pearl:** "Two different blood types/karyotypes in one person" -> chimera; "one zygote, different cell lines due to mitotic error" -> mosaic. Post-HSCT, the patient's blood type and DNA fingerprint can change to match the donor.