2.1 Hematopoietic Lineage, the MHC & HLA Class I vs Class II Biology

Immunology of Transplantation, HLA Matching & Histocompatibility

Quick Clinical Summary: Hematopoietic stem cells generate myeloid and lymphoid lineages whose recovery occurs on different timelines. In allogeneic HCT, allele-level HLA matching at HLA-A, -B, -C, and -DRB1 defines the core 8/8 unrelated-donor match; programs may assess additional loci and permissiveness by current standards. ABO incompatibility does not preclude transplantation, but the mismatch direction informs graft processing and transfusion support.

---

1. Hematopoietic Lineage and Immune Function

A CD34-positive hematopoietic stem and progenitor cell can self-renew and produce two broad developmental branches. The myeloid lineage produces neutrophils, monocytes/macrophages, erythrocytes, megakaryocytes/platelets, eosinophils, basophils, and many dendritic cells. The lymphoid lineage produces T cells, B cells/plasma cells, and natural killer (NK) cells. This map explains why one graft can restore oxygen-carrying capacity, hemostasis, innate defense, and adaptive immunity on different schedules.

Antigen-presenting cells display peptide-HLA complexes to T cells; costimulatory and inflammatory signals determine whether that recognition becomes tolerance, productive immunity, or alloreactivity. Nurses connect the biology to practice by trending lineage recovery, recognizing infection risk that persists after ANC recovery, and distinguishing expected immune reconstitution from graft failure or therapy-related cytopenia.

2. The Major Histocompatibility Complex (MHC) Architecture & Genetics

The Major Histocompatibility Complex (MHC) is a densely clustered region of highly polymorphic genes located on the short arm of chromosome 6 (6p21.3). In humans, the glycoproteins encoded by this cluster are termed Human Leukocyte Antigens (HLA). The primary physiologic function of HLA molecules is to bind peptide fragments derived from pathogens or self-proteins and display them on the cell surface for recognition by antigen-specific T-cell receptors (TCRs).

                    MHC Region on Chromosome 6 (6p21.3)
   [ Centromere ] ── [ Class II ] ─────── [ Class III ] ─────── [ Class I ] ── [ Telomere ]
                     DP  DQ  DR           Complement, TNF       B   C   A

HLA genes exhibit extreme polymorphism—thousands of distinct alleles exist across the human population. They are inherited en bloc as haplotypes in a codominant fashion (one set of maternal alleles and one set of paternal alleles). Because siblings receive one maternal and one paternal haplotype:

• 25% (1 in 4) chance of inheriting identical HLA haplotypes from both parents (HLA-identical sibling donor).
• 50% (1 in 2) chance of sharing one haplotype (haploidentical match).
• 25% (1 in 4) chance of sharing neither haplotype (fully mismatched sibling).

---

3. HLA Class I vs. Class II Antigens: Structure, Distribution & Function

The HLA system is categorized into two principal functional classes that orchestrate cellular immunity:

HLA Class I (HLA-A, HLA-B, HLA-C)

• Molecular Structure: Consists of a polymorphic alpha ($\alpha$) heavy chain (encoded on chromosome 6) non-covalently linked to an invariant $\beta_2$-microglobulin light chain (encoded on chromosome 15).
• Tissue Distribution: Expressed on all nucleated cells and blood platelets (erythrocytes lack significant Class I expression, though they express minor background antigens).
• Immunologic Role: Class I molecules present endogenous peptides (e.g., viral proteins, mutated tumor neoantigens) to CD8+ cytotoxic T lymphocytes (CTLs).
• Transplant Significance: Mismatches at HLA-A, -B, or -C drive CD8+ T-cell-mediated graft rejection and acute GVHD targeting the skin, liver, and gastrointestinal tract.

HLA Class II (HLA-DRB1, HLA-DQB1, HLA-DPB1)

• Molecular Structure: Composed of two polymorphic transmembrane chains: an alpha ($\alpha$) chain and a beta ($\beta$) chain (e.g., DRA/DRB1, DQA1/DQB1, DPA1/DPB1).
• Tissue Distribution: Highly restricted under basal conditions to professional antigen-presenting cells (APCs), including dendritic cells, B-lymphocytes, and macrophages/monocytes, but can be upregulated on vascular endothelial cells and gastrointestinal epithelium under inflammatory cytokine stimulation (e.g., IFN-$\gamma$).
• Immunologic Role: Class II molecules present exogenous antigens (phagocytosed bacteria, extracellular proteins) to CD4+ helper T lymphocytes.
• Transplant Significance: HLA-DRB1 and -DQB1 disparities strongly activate CD4+ alloreactive T cells, initiating the cytokine storm that triggers severe acute and chronic GVHD.

The Clinical Consequence of DPB1 Permissive vs. Non-Permissive Mismatches

HLA-DPB1 is frequently mismatched even in 10/10 matched unrelated donor (MUD) transplants due to a genetic recombination hotspot between DQ and DP. Rather than requiring absolute matching, clinical practice assesses T-cell epitope (TCE) permissiveness:

• Permissive DPB1 mismatches: Share structural homology in the peptide-binding pocket and are immunologically tolerated without significantly increasing non-relapse mortality (NRM).
• Non-permissive DPB1 mismatches: Cause unidirectional or bidirectional alloreactivity, significantly increasing the risk of severe grade III–IV acute GVHD and mortality.

---