T cell BSC

T Cell Interactions Study Notes

Objectives

  • Assess the effect of MHC class I or II deficiency on specific thymocyte populations and the resulting phenotype.

  • Compare how T cell activation by superantigens is different than conventional antigens.

  • Predict the clinical outcome of a TH2 dominant to a TH1 dominant response in Mycobacterium leprae infection and recognize the associated immunologic changes in an individual with a TH2 dominant response.

  • Relate how antibody production by B cells can neutralize extracellular bacteria and viruses and define the isotype important in this response. (Basic Immunology, Chapter 7)

  • Correlate the clinical presentation in the IFN-γ deficiency case to the mechanism of TH1 cell effector function.

References

  • Geha and Rosen, "Case Studies in Immunology, A Clinical Companion"

  • Goudsmit A, Markowicz S, Lali SE, Cherifi S. Food poisoning due to a TSST1-producing Staphylococcus aureus. IDCases. 2021 Sep 1;26:e01272. doi: 10.1016/j.idcr.2021.e01272. PMID: 34584843; PMCID: PMC8455654.

Case Study 1: Tatiana

  • HPI: 17-year-old female with severe bronchiectasis due to chronic respiratory viral infections.

    • Cultured pathogens: Haemophilus influenzae, Streptococcus pneumoniae.

  • Past Medical History: Recurrent respiratory infections since age 4.

  • Medications: Frequent antibiotics for infections.

  • Family History: Younger brother also has similar respiratory infections.

  • Vaccinations: Oral poliovirus, diphtheria, pertussis, tetanus, and BCG vaccine for tuberculosis tolerated well.

  • Laboratory Results:

    • Elevated IgG levels.

    • Normal B, NK, neutrophil populations, and complement levels.

    • CD4 T cells present; severe deficiency in CD8 T cells.

  • Immunological Workup:

    • Adequate response to tuberculin and Candida antigens (normal delayed-type hypersensitivity response).

Case #1 - A Defect in Antigen Presentation

  1. Primary Cell Type for Eliminating Viral Infections:

    • C. CD8+ T cells.

  2. Reduced Expression of Peripheral Blood Mononuclear Cells Marker:

    • Expected reduced expression of HLA A.

  3. Interrupted Process Leading to Deficient CD8+ T Cell Population:

    • D. Positive selection.

  4. Normal Delayed-Type Hypersensitivity Response Explanations:

    • B. The CD4+ T cell response is intact.

  5. Explanation for Tatiana’s High Serum IgG and T Cell Influence on Antibody Responses:

    • CD4+ T cells help B cells produce antibodies, often leading to elevated IgG in absence of CD8+ T cells.

Inheritance of MHC Haplotypes

  • Tatiana's MHC Haplotype: A3 B63 DR4 DQ3.

  • Alexander's MHC Haplotype: Same as Tatiana's, indicating locus deficiency.

  • **Nonsense mutations found in TAP2 gene, affecting MHC class I.

Case #1 - Conclusion

  • No structural/regulatory deficiencies in MHC class I molecules (normal alpha chain mRNA levels).

  • Some immune responses against viruses (e.g., chickenpox, measles, mumps) confirmed; however, she is susceptible to respiratory infections and unable to mount antibody responses against influenza, leading to bronchiectasis.

Case Study 2: Emma

  • HPI: 15-year-old female with severe sore throat, fever, malaise, and difficulty swallowing for 10 days.

  • Past Medical History: Otherwise healthy.

  • Family History: Younger brother mildly affected.

  • Physical Exam:

    • Vital Signs: T 38.2°C, P 84/min, R 18/min, BP 85/55 mmHg.

    • Enlarged tonsils, lymphadenopathy, hepatosplenomegaly.

  • Laboratory Results: WBC 18,590 µl-1:

    • Neutrophils 39%, Lymphocytes 27%, Atypical lymphocytes 22%, Monocytes 11%.

    • Positive IgM and IgG against EBV capsid antigen.

  • Diagnosis: Acute Infectious Mononucleosis.

EBV Immune Response

  • Innate Immune Response: Engagement of Type I interferons and NK cells.

  • Adaptive Immune Response:

    • Antibodies effective during the extracellular stage of viruses.

    • Cytotoxic T Lymphocytes (CTLs) require help from CD4+ T cells to effectively kill infected cells.

  • EBV Replication Cycle: B cells infected with EBV may persist and avoid destruction by CTLs, leading to latent infections.

  • Serological Diagnosis: Heterophile antibodies indicate acute infection; IgG signifies past infection.

Case #2 - Acute Infectious Mononucleosis

  1. Explanation for Unlikely Second EBV Infection:

    • B. IgG antibodies provide protection against recurrent infections.

    • Not IgM because IgM doesn’t contain memory cells

  2. Post-Transplant Lymphoproliferative Disorder Mechanism:

    • D. CTL response downregulation allows uncontrolled EBV growth AND A. Antibody Production

  3. Why In vitro EBV Transformation of B Cells Differs Between Cord Blood and Adults:

    • D. Adults have T cells specific for EBV impacting transformation efficiency.

Evidence of T Cells in Controlling EBV Infection

  1. Deficiencies in T cell immunity can lead to severe EBV infections.

  2. Depleted T cell conditions allow EBV-infected B cells to thrive in vitro.

  3. CTLs can be isolated from patients with acute infectious mononucleosis.

  4. Increased incidence of lymphomas in patients with T cell deficiencies.

Th1 associated with IFN-gamma activation plays a crucial role in enhancing the immune response against viral infections by promoting B cell activation and antibody production.

Th2 associated with IL-4, IL-5, and IL-13 is critical for the regulation of humoral immunity and is instrumental in promoting B cell differentiation, resulting in increased antibody production and allergic responses.

Case Study 3: Ursula

  • HPI: 18-year-old female with hair loss, hypopigmented lesions, and recurrent nosebleeds.

  • Past Medical History: Mild asthma treated with β2-adrenergic agonists.

  • Family History: Mother and others in her town with leprosy.

  • Physical Exam: Neurological deficits with decreased response to stimuli in extremities.

  • Laboratory Results: Normal blood counts, skin biopsy indicated acid-fast bacilli.

Innate and Adaptive Responses to Intracellular Bacteria

  • T Cell Responses:

    • IFN-γ associated with TH1 response.

    • IL-5 and IL-4 associated with TH2 response.

  • Balance of TH1 and TH2 Responses in Mycobacterium leprae Infection:

    • Different immune responses influence clinical outcomes (tuberculoid vs. lepromatous leprosy).

Clinical Characteristics of Leprosy

  • Tuberculoid Leprosy: Strong cell-mediated immunity (CMI) with TH1 response; fewer lesions and good control of Mycobacterium leprae.

  • Lepromatous Leprosy: Weak CMI with TH2 response; numerous lesions, poor control of infection leading to extensive tissue damage.

Case #3 - Lepromatous Leprosy

  1. Beneficial Cytokine for Lepromatous Leprosy Patients: D. IFN-γ.

  2. Mechanism Behind Hypergammaglobulinemia: A. Upregulation by IL-4, IL-5, and IL-13.

  3. Reasons for Possible Asthma Prone Individuals: A. Elevated IL-4 levels.

  4. Other Cellular Deficiency Leading to Susceptibility: C. IFN-γ receptor deficiency.

Toxic Shock Syndrome Case Study

  • Presentation: 15-year-old male with fever, vomiting, rash after consuming fast food. Lab results suggested Staphylococcus aureus infection with evidence of TSST-1 gene.

Case #4 - Toxic Shock Syndrome

  1. Cytokine Responsible for Vascular Depletion: A. TNF-α.

  2. Characteristic T Cell Feature in Toxic Shock: C. Common Vβ chains observed due to superantigen stimulation.

Activation of T Cells by Bacterial Superantigens

  • Mechanism of Superantigen Activation:

    • Polyclonal Activation: Rapid activation of T cell populations by binding to TCR without requiring peptide-MHC recognition.

    • Superantigens induce a widespread T cell activation leading to a cytokine storm and potential deletion of T cells.

Case #5 - IFN-γ Receptor Deficiency

  1. Mutations Leading to Similar Phenotypes in Immunodeficiencies:

    • Treatment with IFN-γ ineffective in patients with: C. IFN-γ receptor 1 mutations.

  2. Clarissa’s Elevated IgG Levels: Immune response against persistent infections.

  3. Immunodeficiency with Similar Pathogen Susceptibility: Potential for chronic granulomatous disease.

  4. Outcomes of Failure to Eliminate Infection: Can result in severe infections and poor prognosis, as seen in Clarissa's case of unaddressed Mycobacterium avium infection.

Delayed-Type Hypersensitivity Reactions

  • Examples: PPD (Purified Protein Derivative) skin test or tuberculin skin test that involves CD4 T cells.

Chronic Delayed-Type Hypersensitivity Responses

  • Develop when infections lead to granuloma formation where macrophages cannot eliminate the pathogen, potentially resulting in tissue damage and fibrosis.