Innate, Adaptive, HLA and Transplant Immunology
- The immune system has two arms. INNATE immunity is the IMMEDIATE, NON-SPECIFIC first line - physical/chemical barriers, PHAGOCYTES (neutrophils and macrophages), NATURAL KILLER (NK) cells and the COMPLEMENT system - and it has NO immunological MEMORY; ADAPTIVE immunity is SLOWER but SPECIFIC and has MEMORY - T LYMPHOCYTES (cell-mediated) and B LYMPHOCYTES that produce ANTIBODIES (humoral immunity).
- The COMPLEMENT system is a cascade of plasma proteins (classical, alternative and lectin pathways converging on C3) that OPSONISES microbes, recruits inflammatory cells (chemotaxis, e.g. C5a), and forms the MEMBRANE ATTACK COMPLEX (C5b-9) to lyse targets - it is part of innate immunity and also contributes to ANTIBODY-MEDIATED (humoral) tissue injury and transplant rejection.
- ADAPTIVE immunity centres on ANTIGEN PRESENTATION via the MAJOR HISTOCOMPATIBILITY COMPLEX (MHC), called HLA in humans: MHC class I (HLA-A/B/C) on all nucleated cells presents to CD8 cytotoxic T cells, and MHC class II (HLA-DR/DQ/DP) on antigen-presenting cells presents to CD4 helper T cells; B cells then make antibodies, and MEMORY cells give a faster, stronger secondary response.
- ALLOGRAFT REJECTION results from recognition of FOREIGN HLA: HYPERACUTE rejection (minutes-hours) is from PRE-FORMED antibodies (e.g. ABO/HLA) activating complement; ACUTE rejection (days-weeks) is T-cell-mediated (cellular) and/or antibody-mediated (humoral, with donor-specific anti-HLA antibodies and complement); CHRONIC rejection (months-years) is a slow fibro-proliferative immune injury - HLA mismatch and donor-specific antibodies drive these processes.
- ORTHOPAEDIC APPLICATION - bone allografts: standard PROCESSED bone allograft (fresh-frozen, freeze-dried/lyophilised, or irradiated) is only WEAKLY IMMUNOGENIC because processing removes/kills the immunogenic cellular and marrow elements, so bone allografts are NOT routinely ABO/HLA matched and act largely as an osteoconductive (and variably osteoinductive) scaffold incorporated by creeping substitution.
- By contrast, FRESH OSTEOCHONDRAL ALLOGRAFTS (transplanted with viable chondrocytes) are MORE IMMUNOGENIC and can provoke a host immune response; the cartilage matrix is relatively immunoprivileged (chondrocytes shielded from immune cells), but exposed subchondral bone/marrow elements and HLA antigens can elicit a response affecting incorporation - a reason fresh osteochondral allografts are used judiciously and are not HLA-matched but are size-matched and used promptly.
- “Innate = immediate, non-specific, NO memory (barriers, phagocytes, NK cells, complement); Adaptive = specific, MEMORY (T cells, B cells/antibodies, MHC/HLA).
- “Complement: opsonisation + chemotaxis (C5a) + membrane attack complex (C5b-9); MHC I -> CD8, MHC II -> CD4.
- “Allograft rejection: hyperacute (pre-formed antibody/complement), acute (cellular T-cell +/- humoral DSA), chronic (fibroproliferative). Processed bone allograft weakly immunogenic (not HLA-matched); fresh osteochondral more immunogenic.
Barriers, phagocytes (neutrophils/macrophages), NK cells, complement. Fast, non-specific, no memory.
T cells (cell-mediated), B cells/antibodies (humoral), MHC/HLA antigen presentation, immunological memory. Slower, specific.
Innate & Adaptive Immunity
Innate immunity is the body's immediate defence: physical and chemical barriers (skin, mucosa), phagocytes (neutrophils and macrophages) that engulf pathogens, natural killer (NK) cells that kill infected/stressed cells, and the complement system; it is rapid and non-specific and has no memory. Adaptive immunity develops over days but is specific and remembers: T lymphocytes mediate cell-mediated immunity (CD4 helper T cells coordinate the response; CD8 cytotoxic T cells kill target cells), while B lymphocytes differentiate into plasma cells that secrete antibodies (humoral immunity), and memory T and B cells provide a faster, stronger response on re-exposure. The two arms are linked - innate cells (especially antigen-presenting cells) instruct the adaptive response.
Complement is a cascade of plasma proteins activated by three pathways - classical (antibody- triggered), alternative and lectin - that converge on C3. Its key effects are OPSONISATION (C3b coats microbes for phagocytosis), CHEMOTAXIS/inflammation (anaphylatoxins such as C5a recruit neutrophils), and the MEMBRANE ATTACK COMPLEX (C5b-9) that lyses target cells. As an innate mechanism it defends against infection, but it is also a major effector of antibody-mediated (humoral) tissue injury, including in transplant rejection, where donor-specific antibodies fix complement on graft endothelium.
MHC/HLA & Antigen Presentation
The major histocompatibility complex (MHC) - the human leukocyte antigen (HLA) system - presents peptide antigens to T cells and is the basis of allorecognition. MHC class I (HLA-A, -B, -C) is on all nucleated cells and presents intracellular peptides to CD8 cytotoxic T cells; MHC class II (HLA-DR, -DQ, -DP) is on antigen-presenting cells (dendritic cells, macrophages, B cells) and presents extracellular peptides to CD4 helper T cells, which then orchestrate the B-cell antibody response and cytotoxic responses. Because HLA is highly polymorphic, an individual's HLA is recognised as foreign by another's immune system - the central problem in transplantation. (HLA associations are also high-yield in rheumatology, e.g. HLA-B27 with the seronegative spondyloarthropathies.)
Allograft Rejection & Orthopaedic Application
- Hyperacute (minutes-hours): PRE-FORMED recipient antibodies (e.g. ABO or anti-HLA) bind donor endothelium and activate complement -> rapid thrombosis/graft loss.
- Acute (days-weeks): cellular (T-cell-mediated) and/or humoral/antibody-mediated rejection (donor-specific anti-HLA antibodies, DSA, with complement) - the main form prevented by immunosuppression in solid-organ transplants.
- Chronic (months-years): a slow fibro-proliferative immune-mediated injury causing graft fibrosis and failure. HLA mismatch and donor-specific antibodies drive these processes; NK cells (via KIR-HLA interactions) also contribute.
- Processed bone allograft (fresh-frozen, freeze-dried/lyophilised, irradiated) is only WEAKLY IMMUNOGENIC: processing removes or kills the immunogenic cells and marrow, leaving a largely acellular matrix that acts as an osteoconductive (and variably osteoinductive) scaffold incorporated by creeping substitution. For this reason bone allografts are NOT routinely ABO/HLA matched - unlike solid organs - and immunosuppression is not used.
- Fresh OSTEOCHONDRAL allograft (transplanted with viable chondrocytes) is MORE immunogenic: the hyaline cartilage matrix is relatively immunoprivileged (chondrocytes are shielded within matrix from immune cells), but exposed subchondral bone/marrow and HLA antigens can provoke a host response that may affect incorporation; these grafts are size-matched and used promptly but are not HLA-matched.
- Implant materials and wear debris also engage the immune system (e.g. macrophage-driven osteolysis, metal hypersensitivity) - see our Wear/Osteolysis and Metal Hypersensitivity topics.
Evidence & Key Studies
KIR and their HLA class I ligands in chronic rejection and graft loss in transplantation
- Incompatibility between donor and recipient for HLA (MHC) class I generates complex cellular and humoral immune responses largely responsible for rejection and graft loss.
- Alloreactive natural killer (NK) cells, regulated by killer immunoglobulin-like receptors (KIR) interacting with HLA class I, contribute to rejection - linking innate (NK) and adaptive (HLA) immunity.
- Demonstrates that HLA matching and KIR-HLA combinations influence rejection risk - the immunological basis of allorecognition.
Consensus recommendations on donor-specific anti-HLA antibodies (DSA) in transplantation
- Donor-specific anti-HLA antibodies (DSA) are an important cause of graft (engraftment) failure, reflecting antibody-mediated (humoral) rejection.
- DSA are detected by multiplex bead arrays and complement-binding (C1q) assays, linking antibody, HLA and the complement cascade.
- Higher DSA levels confer higher rejection/failure risk, and desensitization removes/neutralises antibodies and inhibits complement activation - illustrating humoral allorejection mechanisms.
According to PubMed, the role of HLA (MHC) class I mismatch in cellular and humoral rejection and the contribution of NK cells/KIR come from the cited Littera study, and the role of donor-specific anti-HLA antibodies and complement in antibody-mediated rejection from the cited Kongtim consensus. The innate/adaptive framework, complement cascade, MHC/HLA antigen presentation and the immunogenicity of processed bone versus fresh osteochondral allografts are standard, well-established teaching. (See also our Inflammation/Cytokines, Bone Grafts and Osteochondral Allograft topics.)
Clinical Decision Scenarios
Practise clinical reasoning and management decisions out loud
“Outline the difference between innate and adaptive immunity, and explain the role of complement and MHC/HLA.”
“Why are bone allografts not HLA-matched, and how does this differ for fresh osteochondral allografts?”
Mnemonics & Memory Aids
INNATE
Hook:INNATE = immediate, non-specific, no memory.
MHC 1-8 / 2-4
Hook:Rule of 8: MHC I x CD8 = 8; MHC II x CD4 = 8.
Innate immunity
- Immediate, non-specific, NO memory
- Barriers, phagocytes (neutrophils/macrophages), NK cells, complement
- Complement: opsonisation (C3b), chemotaxis (C5a), membrane attack complex (C5b-9)
Adaptive immunity
- Specific, has MEMORY
- T cells (CD4 helper, CD8 cytotoxic) - cell-mediated; B cells -> antibodies (humoral)
- MHC I (HLA-A/B/C) -> CD8; MHC II (HLA-DR/DQ/DP) -> CD4
Allograft rejection
- Hyperacute: pre-formed antibody + complement (minutes-hours)
- Acute: cellular (T-cell) +/- humoral (DSA + complement) (days-weeks)
- Chronic: fibro-proliferative immune injury (months-years)
Orthopaedic allografts
- Processed bone allograft: weakly immunogenic - NOT HLA-matched; osteoconductive scaffold (creeping substitution)
- Fresh osteochondral allograft: viable chondrocytes - more immunogenic; cartilage relatively immunoprivileged
- Osteochondral grafts size-matched + used promptly (not HLA-matched)