Immunodeficiencies LO5

Introduction to Lymphocyte Activation Deficiencies

  • Overview of T cell and B cell activation defects leading to immunodeficiencies.

  • Importance of the role of lymphocyte activation in the immune response.

  • Differences between two studied deficiencies: a well-characterized immunodeficiency and a unique case study involving only three patients.

Types of Deficiencies in Lymphocyte Activation

  • Various genetic mutations can lead to immunodeficiencies characterized by:

    • Normal lymphocyte numbers.

    • Dysfunctional lymphocyte activation, resulting in impaired immune response.

  • Potential implications of these defects:

    • Defects in Th17 immunity resulting in susceptibility to extracellular bacteria due to a failure in attracting neutrophils.

    • Defects in Th1 immunity leading to poor macrophage activation.

    • Various B cell defects affecting humoral immunity, including:

    • Common variable immunodeficiencies.

    • X-linked hyper IgM syndrome.

    • Other deficiencies impairing antibody production in plasma cells.

Focus on X-Linked Hyper IgM Syndrome

  • Formal name: X-linked agammaglobulinemia with hyper IgM.

    • Characteristics include:

    • Extremely high levels of IgM.

    • Very low or absent levels of IgG, IgA, and IgE.

    • Presence of plasma cells, but absence of germinal center reactions observed histologically in the spleen and lymph nodes.

    • Germinal centers are necessary for isotype switching to produce IgG, IgA, and IgE.

  • Clinical implications:

    • Patients suffer recurrent pyogenic bacterial infections (e.g., infections caused by Haemophilus influenzae, various streptococci, Staphylococcus aureus).

    • Some susceptibility to opportunistic intracellular pathogens due to broader roles of the defective gene in immunity.

  • Lymphocyte count:

    • Patients typically present with normal blood lymphocytes, although some may exhibit neutropenia.

  • Treatment options include:

    • Intravenous gamma globulin.

    • Prophylactic antibiotics.

    • Haemopoietic stem cell transplantation (HSCT), equivalent to bone marrow transplantation.

  • Histological evidence in X-linked hyper IgM patients:

    • Contrast between normal lymph nodes displaying active germinal centers and those in hyper IgM patients showing no germinal centers.

Isotype Switching Overview

  • Isotype switching process:

    • Initial antibody is IgM during primary immune responses, peaking 7-10 days post immunization/infection.

    • Transition occurs to IgG, peaking around two weeks, followed by the generation of memory cells.

    • Predominant isotype during early responses is IgM, switching later to IgG, IgA, or IgE based on the immune context.

  • Isotype switching requires T cell help:

    • Limited isotype switching occurs without T cell assistance.

    • Interferon-gamma (IFN-γ) leads to IgG production, IL-4 to IgE, and TGF-beta influences IgA production.

  • Critical signaling molecules:

    • Interaction between CD40 on B cells and CD40 ligand (CD40L) on T cells is essential for B cell activation, proliferation, and differentiation.

    • CD40L is the mutated gene responsible for X-linked hyper IgM syndrome.

    • Rare mutations may also involve CD40 on B cells, requiring two defective copies for a phenotype to manifest.

Importance and Limitations of IgM

  • IgM: Effective in activating complement and providing a degree of humoral immunity.

    • While patients retain some level of IgM, they lack the neutralizing function provided by IgG and IgA, leading to recurring infections.

Case Study: CD28 Deficiency and Treeman Syndrome

  • Presentation of a unique case study about CD28 deficiency:

    • A 30-year-old Iranian patient with Treeman syndrome.

    • Characteristics of Treeman syndrome:

    • Severe hyperkeratotic cutaneous papillomatosis (non-control of warts).

    • Association with human papillomavirus (HPV) types 2 and 4.

    • Relative prevalence of Treeman syndrome:

    • Only four unrelated cases documented.

  • Clinical investigation of immune function:

    • Normal counts of most immune cell types (monocytes, dendritic cells, B cells) observed.

    • Minor T cell and NK cell perturbations.

    • Normal antibody responses and no clinical signs of autoimmunity, suggesting a specific defect.

  • Genetic findings:

    • Identification of CD28 expression failure as the primary defect.

  • Implications of CD28 deficiency:

    • Traditionally regarded as a significant regulator for T cell activation via co-stimulation and generally linked to severe immunodeficiency.

  • Conundrum Presented:

    • Despite the absence of CD28, patients only exhibit susceptibility to specific viruses (HPV) rather than a broad immunodeficiency with numerous infections.

  • Explanation via functional redundancy:

    • Other surface molecules on T cells can take over the co-stimulatory function typically performed by CD28.

    • The immune system may adapt, leading to normal responses except where CD28's specific signaling is crucial (e.g., for HPV).

Conclusion

  • Summary of genetic defects leading to lymphocyte activation failures.

  • Distinction between primary and secondary immunodeficiencies.

  • Importance of understanding genetic mutations in the context of clinical outcomes and treatments.

  • Comprehensive grasp of diverse mechanisms leading to immunodeficiencies and their implications for patient care.