2.4: Immunology & Immunotherapy

2.4: Immunology & Immunotherapy

The human immune system is a complex, multi-layered network designed to protect the host from pathogens, clear aberrant cells, and maintain homeostasis. For the OPRA exam, a pharmacist must understand the molecular and cellular mechanics of immunology, including immunoglobulin classes, the kinetics of primary and secondary immune responses, vaccine technology, and the pathophysiology and pharmacological management of autoimmune diseases.

1. Innate vs. Adaptive Immunity

Immunity is divided into innate (non-specific) and adaptive (specific) responses. Innate immunity provides immediate defense through physical barriers (skin, mucous membranes), chemical barriers (stomach acid, lysozymes), and cellular components (neutrophils, macrophages, natural killer cells). It lacks immunological memory. Adaptive immunity is antigen-specific, takes days to develop, and is mediated by T-lymphocytes (cell-mediated immunity) and B-lymphocytes (humoral immunity), which generate immunological memory.

2. Immunoglobulin Structure and Classifications

Immunoglobulins (antibodies) are Y-shaped glycoproteins produced by plasma cells (differentiated B-lymphocytes). They consist of two heavy chains and two light chains held together by disulfide bonds, featuring a constant region (Fc, which determines biological activity) and a variable region (Fab, which binds specific antigens).

There are five primary classes of immunoglobulins, each with distinct structures, distributions, and clinical roles:

3. Primary vs. Secondary Immune Responses

The kinetics of antibody production differ dramatically between initial exposure to a pathogen and subsequent exposures.

• Primary Immune Response: Occurs upon first exposure to an antigen. There is a lag phase of approximately 7 to 10 days before antibodies are detectable in serum. During this phase, naive B cells bind the antigen, undergo clonal expansion, and differentiate. The first antibody isotype secreted is IgM, followed by a gradual increase in IgG. The peak antibody titre is relatively low, and the antibodies have moderate affinity for the antigen.
• Secondary Immune Response: Occurs upon subsequent exposure to the same antigen. The lag phase is significantly reduced to 1 to 3 days. Memory B cells created during the primary response rapidly proliferate and differentiate into plasma cells. This response is dominated by a rapid and massive production of IgG with much higher affinity for the antigen (affinity maturation). This isotype switching is mediated by CD4+ T helper cells and cytokine signalling.

4. Vaccine Classification and Clinical Application

Vaccines stimulate active immunity by exposing the immune system to a non-pathogenic form of an antigen. The Australian Immunisation Handbook (AIH) classifies vaccines based on their composition, which determines their safety profile, dosing schedule, and suitability for specific patient cohorts.

A. Live Attenuated Vaccines

Live attenuated vaccines contain pathogens that have been weakened in a laboratory so they can replicate within the host but do not cause disease in healthy individuals.

• Immunological mechanism: Mimics a natural infection, inducing strong humoral and cell-mediated immunity, often providing lifelong protection with one or two doses.
• Examples: Measles, Mumps, Rubella (MMR), Varicella (chickenpox), Yellow Fever, Rotavirus.
• Clinical Precautions & Contraindications: Live vaccines must never be administered to pregnant women (due to the theoretical risk of congenital infection) or severely immunocompromised individuals (e.g., patients on chemotherapy, advanced HIV, or biological DMARDs like adalimumab or infliximab). High-dose systemic corticosteroids (prednisolone >= 20 mg/day or >= 2 mg/kg/day for more than 14 days) also contraindicate live vaccines; a washout period of at least 3 months is generally required after stopping immunosuppressive doses before a live vaccine can be administered.
• Cold Chain: Must be stored strictly between +2°C and +8°C under the National Vaccine Storage Guidelines ("Strive for 5"). Freezing live attenuated vaccines can destroy their efficacy.

B. Inactivated and Subunit Vaccines

These contain killed pathogens or purified immunogenic parts (proteins, polysaccharides, or recombinant proteins).

• Immunological mechanism: Do not replicate inside the host. They are safe for immunocompromised patients but generally require an adjuvant (to boost immunogenicity) and multiple booster doses to maintain protective antibody titres.
• Examples: Infanrix Hexa (DTaP-HepB-IPV-Hib), Pneumovax 23 (pneumococcal polysaccharide), Prevenar 13/20 (pneumococcal conjugate), Shingrix (recombinant subunit shingles vaccine).
• Clinical Pearl (Zostavax vs. Shingrix): In November 2023, the recombinant subunit vaccine Shingrix replaced the live attenuated vaccine Zostavax on the National Immunisation Program (NIP) in Australia. Shingrix provides superior protection against herpes zoster and post-herpetic neuralgia and, being non-live, is safe for use in immunocompromised patients who were previously at risk of fatal disseminated varicella-zoster virus infection from Zostavax.

C. mRNA Vaccines

mRNA vaccines deliver a synthetic mRNA sequence enclosed in lipid nanoparticles into host cells.

• Immunological mechanism: Host cell ribosomes translate the mRNA into a viral protein (e.g., the SARS-CoV-2 spike protein). The protein is then presented on the cell surface via MHC Class I and II molecules, triggering a robust T-cell and B-cell response. The mRNA is rapidly degraded and does not enter the cell nucleus or integrate into the host genome.
• Examples: Comirnaty (Pfizer), Spikevax (Moderna).
• Safety considerations: Linked to a small risk of myocarditis and pericarditis, primarily in males aged 12–30 years, typically within 14 days of the second dose.

5. Autoimmune Disease Mechanisms & Hypersensitivity

Autoimmunity occurs when the immune system loses self-tolerance, leading to targeted damage of host tissues. This tissue destruction is categorized by the Gell and Coombs hypersensitivity classification:

• Type I (Immediate): IgE-mediated mast cell degranulation (e.g., anaphylaxis).
• Type II (Antibody-mediated cytotoxic): Antibodies bind to self-antigens on cell surfaces (e.g., Myasthenia Gravis, where autoantibodies block or destroy nicotinic acetylcholine receptors at the neuromuscular junction, causing progressive muscle weakness).
• Type III (Immune complex-mediated): Circulating antigen-antibody complexes deposit in vessel walls and tissues, activating complement and causing inflammatory damage (e.g., Systemic Lupus Erythematosus [SLE], where anti-dsDNA antibodies form complexes that deposit in renal glomeruli, leading to lupus nephritis).
• Type IV (Cell-mediated / Delayed): Mediated by T-lymphocytes rather than antibodies (e.g., Rheumatoid Arthritis [RA], where CD4+ T helper cells and macrophages infiltrate the synovium, secreting pro-inflammatory cytokines like TNF-alpha and IL-6, causing joint destruction).

Immunotherapeutic Principles

Pharmacological management of autoimmune diseases aims to suppress aberrant immune responses:

1. Corticosteroids: Provide rapid, non-specific anti-inflammatory effects by inhibiting NF-kB and arachidonic acid pathways.
2. Conventional Synthetic DMARDs (csDMARDs): E.g., methotrexate (folate antagonist), sulfasalazine, leflunomide.
3. Biological DMARDs (bDMARDs): Target specific cytokines (e.g., TNF-alpha inhibitors like adalimumab, infliximab; IL-6 inhibitors like tocilizumab) or deplete specific immune cells (e.g., rituximab, which targets CD20 on B-lymphocytes).
4. Clinical Pre-Screening Requirements: Before commencing biological therapies in Australia, pharmacists must ensure the patient has been screened for:
   • Latent Tuberculosis: Commencing a biologic can reactivate latent TB. A QuantiFERON-TB Gold test or tuberculin skin test must be performed. If positive, latent TB treatment must be completed before starting the biologic.
   • Hepatitis B and C: To prevent viral reactivation.
   • Vaccinations: All indicated live vaccines must be administered at least 4 weeks before starting biological DMARDs, as live vaccines are contraindicated once therapy commences.