Immunology in Orthopaedics (Innate, Adaptive, HLA & Transplant Immunology)

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.

• 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.

Innate and adaptive immunity, complement, rejection and metal hypersensitivity are tied together by one framework - the Gell & Coombs hypersensitivity classification, core applied-basic-science viva material:

• Type I (immediate, IgE-mediated): allergen cross-links IgE on mast cells → degranulation (histamine) → anaphylaxis/urticaria within minutes. Orthopaedic examples: latex allergy, drug/antibiotic anaphylaxis.
• Type II (antibody-mediated, cytotoxic): IgG/IgM against cell-surface antigens, activating complement and ADCC. Examples: transfusion (ABO) reactions, hyperacute graft rejection, autoimmune cytopenias.
• Type III (immune-complex): circulating antigen-antibody complexes deposit in tissues and fix complement → vasculitis/synovitis. Examples: rheumatoid arthritis, SLE, serum sickness.
• Type IV (delayed, cell-mediated): T-cell/macrophage response peaking at 48 to 72 hours, with no antibody. Examples: metal hypersensitivity (nickel/cobalt-chromium implant reactions, including ALVAL - an aseptic lymphocyte-dominated vasculitis-associated lesion - around metal-on-metal implants), contact dermatitis, the tuberculin (Mantoux) skin test, and acute cellular transplant rejection.

The orthopaedic punchline: metal hypersensitivity / ALVAL is Type IV, hyperacute rejection is Type II, and the inflammatory arthropathies (RA, SLE) involve Type III. (Implant metal hypersensitivity and ALVAL in depth belong to our Metal Hypersensitivity / Wear-Osteolysis topics; here is the framework.)

An "immunology in orthopaedics" topic must also cover the patient's own immune competence, which changes peri-operative decisions:

• The immunosuppressed / on-biologics patient: disease-modifying biologics (anti-TNF, anti-IL-6, rituximab) and corticosteroids raise the infection risk of surgery. The usual approach is to hold biologic agents around surgery (timed to the drug's dosing cycle) to reduce infection while balancing a disease flare, often continue methotrexate, and give peri-operative steroid cover for those on long-term steroids; restart biologics once the wound is healing and there is no infection.
• The asplenic / hyposplenic patient (e.g. after post-traumatic splenectomy): loss of the spleen's filtering and antibody function leaves a lifelong risk of overwhelming post-splenectomy infection (OPSI) from encapsulated organisms (pneumococcus, meningococcus, Haemophilus). Manage with vaccination against these organisms (ideally before, or after, splenectomy), antibiotic prophylaxis/standby, and patient education - relevant whenever the orthopaedic/trauma team is responsible for such a patient.
• General principle: the immunocompromised surgical patient (also diabetes, chemotherapy, transplant immunosuppression) has a higher infection risk and a blunted response, demanding meticulous antisepsis, optimisation, and a low threshold for investigating infection.

(The cytokines and their inhibitors are covered in our Inflammation/Cytokines topic; the point here is the peri-operative immune status.)

Polyethylene wear particles are the wrong size and the wrong chemistry for the immune system. They are small enough to be ingested by macrophages and impossible to degrade, so the macrophage mounts a response it can never complete - the classic frustrated phagocytosis - and keeps signalling.

The sequence is worth knowing in order because each step is a place the process could be interrupted:

1. Particles are phagocytosed by periprosthetic macrophages, which cannot digest them.
2. Inflammatory cytokines are released - TNF-alpha, IL-1, IL-6 and PGE2 - producing a chronic, self-sustaining inflammatory membrane at the bone-implant interface.
3. RANKL rises relative to osteoprotegerin (OPG). OPG is the decoy receptor that normally mops RANKL up, so what matters is the RANKL/OPG ratio, not RANKL alone.
4. RANKL binds RANK on osteoclast precursors, driving their differentiation and activation.
5. Osteoclasts resorb bone around a prosthesis that is still perfectly well fixed - producing the expanding, non-infective lucency of periprosthetic osteolysis, and eventually aseptic loosening.

Why this matters for a decision you actually make: every intervention that has reduced osteolysis works at step 1, by reducing the particle burden - crosslinking the polyethylene above all. Nothing works at steps 2 to 5, because there is no licensed way to interrupt the immune response itself, and attempts to repurpose antiresorptives have not changed practice. Bearing choice is the immunological intervention.

Implant infection behaves unlike infection in native tissue, and the reason is immunological rather than microbiological. An implant surface has no blood supply, so the cellular and humoral defences that clear bacteria elsewhere reach it poorly. Neutrophils that do arrive are functionally impaired at a foreign surface, and organisms within a mature biofilm are metabolically quiescent, physically shielded by their matrix, and therefore invisible both to those defences and to antibiotics that require dividing cells.

Three consequences follow directly, and they explain the whole management algorithm:

• Host defence will not clear it, and nor will antibiotics alone, however long they are given. The question is surgical from the outset.
• Biofilm maturity, not symptom duration alone, drives the decision between debridement with implant retention and exchange of the implant.
• Biofilm-active agents matter - rifampicin combinations for staphylococci, and never rifampicin as monotherapy because resistance emerges rapidly.

The unifying idea across both halves of this section: in orthopaedics the immune system is usually failing not because it is deficient but because it has been asked to deal with something it cannot remove, in a place it cannot reach.