Case Presentation:
- History: A 38 year old man has had a worsening cough for the past month. There is a small amount of sputum production. He has had episodes of fever. He has had a 5 kg weight loss over the past two months. A chest radiograph reveals a reticulonodular pattern, particularly in the upper lung fields. A sputum sample is sent for gram stain, routine culture, and acid fast stain. The gram stain and the culture reveal normal upper respiratory tract flora, but the acid fast stain is positive.
- What disease is he most likely to have?
- Tuberculosis.
- What infectious agent is involved?
- The most likely organism is Mycobacterium tuberculosis.
Mycobacterium tuberculosis in lung, Ziehl-Neelsen acid fast stain.
- What immune response is needed to control this infection?
- When mycobacteria are inhaled, they are of a size that allows them to reach the alveoli, where they can proliferate. Initial responses of the innate immune system are inadequate because of the thick lipid coat of these organisms that resists degradation. PMNs blast away at them with their lysosomal granules, but are ineffective. Mycobacteria can proliferate within ordinary macrophages that ingest them.
- How is this immune response generated?
- Processed mycobacterial antigens from the macrophages (the major antigen presenting cell involved) reaches naïve T cells that are specific for the mycobacterial antigens. Both class I and class II MHC molecules are involved. The MHC class I and II molecules expressed on macrophages activate the T cells in the presence of a costimulator. CD40 ligand on T cells binds to CD40 on macrophages to increase production of both costimulators and cytokines.
- Animation: antigen presenting cell and CD8 cell interaction.
- Presence of activated CD4 "helper" cells can activate CD8 cells. These activated T cells secrete cytokines that cause a clonal expansion of T cells, most of which become effector T cells that go to the site of infection, while some remain as memory T cells and persist for years. Cytokines called chemokines bind to chemokine receptors and signal T cell integrins to provide high affinity binding to antigen presenting cells.
- Additionally, effector T cells express adhesion molecules that aid in binding to selectins on endothelium in areas where cytokines act as chemoattractants that draw the lymphocytes into the tissues. This process is non-selective, but those effector cells that recognize the appropriate antigen stay and become activated by antigen. Effector cells become active with minimal costimulation.
- The T cell receptor (TCR) is actually a complex that includes the alpha and beta chains of TCR that recognize the antigen, as well as a gamma chain and a CD3 protein on the surface of lymphocytes that aids in tyrosine kinase signalling to activate nuclear transcription. One such pathway is calcium dependent, with binding to calmodulin, which activates calcineurin. The drug cyclosporine binds to calcineurin to inhibit cytokine production and blunt the immune response, a useful process to prevent transplant rejection.
- How long does this process take to develop?
- Within hours of activation, CD4 cells begin producing interleukin-2, which has an autocrine and paracrine effect to stimulate T cell proliferation. Within 24 to 48 hours, the number of antigen-specific T cells has increased 10,000-fold. Once this initial response is generated, the process of containing the infection may take weeks to months.
- What other cells are involved?
- CD4 cells secrete cytokines that activate macrophages and B cells. Different CD4 cells secrete different cytokines to produce different types of immune responses, based upon the type of antigen present. There can be a TH1 response, with significant production of interferon gamma, or a TH2 response, with production of IL-4 and IL-5 that promote allertic responses with IgE and eosinophils. The TH1 and TH2 subsets also express different chemokine receptors.
- With mycobacterial infection, TH1 cytokines are secreted, specifically interferon gamma, that cause macrophages to come together and form giant cells that are more effective in killing the mycobacteria. Interferon gamma along with CD40 ligand binding to macrophages triggers transcription of macrophage genes that direct enhanced microbial killing by substances such as reactive oxygen intermediates and nitric oxide.
- What histologic appearance is seen with this immune response?
- The result of a successful response to mycobacterial infection is a granuloma. This type of inflammatory response persists or increases as long as mycobacteria continue to proliferate. Once the infection is contained, stimuli to lymphocyte activation diminish, and effector cells undergo apoptosis, leaving memory cells behind.
Microscopic appearance of granulomas in the lung
- How do the organisms resist destruction?
- Mycobacteria have evolved to resist destruction by inhibiting the fusion of the phagosome containing them with a lysosome, so that a phagolysosome is not formed.
- What is the mechanism by which past infection is diagnosed?
- Rechallenge of the immune system later with mycobacterial antigen elicits a response, based upon activation of the memory T cells. This second response is called a delayed type hypersensitivity reaction-delayed in that it takes 1 to 3 days for the inflammatory response to become apparent. This is the basis for the tuberculin skin test.
- How is it possible that T cells can react with so many potentially different infectious agents?
- During development of the immune system, as the T cells were proliferating, they had genes that determined the makeup of T cell receptors (TCRs). These genes consisted of variable (V), diversity (D), and joining (J) genes that underwent recombination to produce extensive variability in the TCRs. There is even more diversity as a result of variability in the nucleotide sequences of the junctions between the V, D, and J regions. An enzyme called terminal deoxyribonucleotidyl transferase (TdT) randomly adds nucleotides to junctions of V, D, and J regions. The multitude of VDJ combinations in the T cells provides for tremendous diversity and the ability of T cells to respond to any possible antigenic challenge. The number of possible combinations is 1016.
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