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

Innate immunity. The body's immediate defence is made of physical and chemical barriers (skin, mucosa), phagocytes (neutrophils and macrophages) that engulf pathogens, natural killer (NK) cells that kill infected or stressed cells, and the complement system. It is rapid and non-specific, and it has no memory.

Adaptive immunity. It develops over days, but it is specific and it remembers. T lymphocytes mediate cell-mediated immunity: CD4 helper T cells coordinate the response and CD8 cytotoxic T cells kill target cells. 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.

How the arms connect. Innate cells, especially antigen-presenting cells, instruct the adaptive response.

Complement. Complement is a cascade of plasma proteins activated by three pathways, classical (antibody-triggered), alternative and lectin, which converge on C3. It has three key effects:

• Opsonisation - C3b coats microbes for phagocytosis
• Chemotaxis and inflammation - anaphylatoxins such as C5a recruit neutrophils
• Membrane attack complex (C5b-9) - lyses target cells

Complement in rejection. As an innate mechanism complement defends against infection, but it is also a major effector of antibody-mediated (humoral) tissue injury. That includes transplant rejection, where donor-specific antibodies fix complement on graft endothelium.

What HLA does. The major histocompatibility complex (MHC), the human leukocyte antigen (HLA) system in humans, presents peptide antigens to T cells and is the basis of allorecognition. It comes in two classes:

• 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

View larger

Polymorphism. Because HLA is highly polymorphic, one individual's HLA is recognised as foreign by another's immune system, and that is the central problem in transplantation. HLA associations are also high-yield in rheumatology, HLA-B27 with the seronegative spondyloarthropathies for example.

Rejection. HLA mismatch and donor-specific antibodies drive rejection, and NK cells, through KIR-HLA interactions, also contribute. It is classified by when it occurs:

• Hyperacute (minutes-hours) - pre-formed recipient antibodies (ABO or anti-HLA, for example) bind donor endothelium and activate complement, causing rapid thrombosis/graft loss
• Acute (days-weeks) - cellular (T-cell-mediated) and/or humoral (antibody-mediated) rejection, the humoral form through donor-specific anti-HLA antibodies (DSA) with complement; this is 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

Processed bone allograft. Fresh-frozen, freeze-dried (lyophilised) or irradiated bone allograft 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, it is more immunogenic. The hyaline cartilage matrix is relatively immunoprivileged, the chondrocytes being shielded within it from immune cells, but exposed subchondral bone and marrow, and HLA antigens, can provoke a host response that may affect incorporation. These grafts are size-matched and used promptly, but they are not HLA-matched.

Implants. Implant materials and wear debris also engage the immune system, through macrophage-driven osteolysis and metal hypersensitivity for example. Both are covered in depth in the Wear/Osteolysis and Metal Hypersensitivity topics.

One framework. The Gell & Coombs hypersensitivity classification ties innate and adaptive immunity, complement, rejection and metal hypersensitivity together, and it is core applied-basic-science viva material.

• Type I (immediate, IgE-mediated). Allergen cross-links IgE on mast cells, which degranulate (histamine), producing anaphylaxis or urticaria within minutes. The orthopaedic examples are latex allergy and drug or antibiotic anaphylaxis.
• Type II (antibody-mediated, cytotoxic). IgG or IgM against cell-surface antigens activates complement and ADCC. Examples are transfusion (ABO) reactions, hyperacute graft rejection and autoimmune cytopenias.
• Type III (immune-complex). Circulating antigen-antibody complexes deposit in tissues and fix complement, producing vasculitis or synovitis. Examples are rheumatoid arthritis, SLE and serum sickness.
• Type IV (delayed, cell-mediated). A T-cell and macrophage response peaking at 48 to 72 hours, with no antibody. Examples are 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 patient's own immune competence changes peri-operative decisions. The cytokines and their inhibitors are covered in the Inflammation/Cytokines topic; the point here is peri-operative immune status.

Biologics and steroids. 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. Methotrexate is often continued, those on long-term steroids are given peri-operative steroid cover, and biologics restart once the wound is healing and there is no infection.

The asplenic or hyposplenic patient. After post-traumatic splenectomy, for example, loss of the spleen's filtering and antibody function leaves a lifelong risk of overwhelming post-splenectomy infection (OPSI) from encapsulated organisms: pneumococcus, meningococcus and Haemophilus. Management is vaccination against these organisms (ideally before, or after, splenectomy), antibiotic prophylaxis or standby, and patient education. This is relevant whenever the orthopaedic or trauma team is responsible for such a patient.

The general principle. The immunocompromised surgical patient, including those with diabetes, on chemotherapy or on transplant immunosuppression, has a higher infection risk and a blunted response. That demands meticulous antisepsis, optimisation and a low threshold for investigating infection.

Most immunology taught to surgeons is transplant immunology borrowed from other specialties. The two immune responses that actually determine orthopaedic outcomes are different, and neither involves a donor: both are reactions to a piece of inert material the body cannot remove.

Wear particles and frustrated phagocytosis. 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. Each step is a place the process could be interrupted, which is why the order is worth knowing:

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 it matters. 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.

Biofilm, an immunologically privileged surface. 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.

Why the defences fail. Neutrophils that do arrive are functionally impaired at a foreign surface. Organisms within a mature biofilm are metabolically quiescent and physically shielded by their matrix, and therefore invisible both to those defences and to antibiotics that require dividing cells.

The consequences. Three 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. 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.