MHC Deficiency

Introduction

Major Histocompatibility Complex (MHC) deficiency refers to a group of rare genetic disorders that result in impaired or absent expression of MHC molecules on the surface of cells. MHC molecules are crucial for the immune system’s recognition of self and non-self antigens, making MHC deficiency a significant concern for immune function. Understanding MHC deficiency is essential for medical professionals, especially those in immunology, genetics, and pediatrics. This article provides a comprehensive overview of MHC deficiency, including its types, function, related studies, treatment considerations, and clinical significance.

Snapshot

• An infant child is brought to the pediatrician for the evaluation of recurrent infections. The mother reports that her child has been having frequent respiratory and skin infection. The mother is not aware of any diseases that run in the family that will result in an increased susceptibility to infection. A ↓ MHC class 1 expression on peripheral blood mononuclear cells is noted on flow cytometry. Further genetic testing shows the infant has a mutation in the tapasin protein. (MHC class I deficiency)

MHC Class I Deficiency (Bare Lymphocyte Syndrome Type I)

• Clinical definition
  • an immunodeficiency syndrome secondary to defects in
    • TAP 1, TAP 2, and tapasin which are involved in
      • transporting the antigen peptide (TAP 1 and 2) into the endoplasmic reticulum and
        • loading (tapasin) the antigen peptide into the MHC
• Presentation
  • frequent bacterial infections such as
    • upper and lower respiratory infections
    • skin infections
• Laboratory findings
  • ↓ or decreased MHC class I expression
  • ↓ NK cell killing activity
  • ↓ CD8+ T-cells
• Differential
  • other immunodeficiency syndromes such as
    • common variable immunodeficiency
• Diagnosis
  • definitive diagnosis is accomplished with
    • flow cytometry, which shows
      • ↓ MHC I expression on peripheral blood mononuclear cells
• Treatment
  • management focuses on controlling the infection with
• antibiotics

MHC Class II Deficiency (Bare Lymphocyte Syndrome Type II)

• Clinical definition
  • an immunodeficiency syndrome possibly secondary to defects in
    • DNA-binding regulatory molecules of the class II MHC promoter
• Presentation
  • infections with
    • viruses
    • bacteria
    • fungi
    • protozoa
  • the clinical scenario may be similar to severe combined immunodeficiency (SCID) because
    • MHC class II plays an important role in
      • the maturation and functioning of
        • T- and B-cells
• Laboratory findings 
  • normal number of T- and B-cells in the peripheral blood
  • hypogammaglobulinemia
  • absence of MHC class II on B cells
  • ↓ CD4+ T-cells
• Differential
  • other immunodeficiency syndromes such as
    • SCID
• Diagnosis
  • definitive diagnosis is accomplished with
    • flow cytometry, which shows
      • ↓ MHC II expression on peripheral blood mononuclear cells
• Treatment
  • management focuses on controlling the infection with
  • antibiotics and immunoglobulin therapy

Types of MHC Deficiency:

1. MHC Class I Deficiency: Also known as bare lymphocyte syndrome type I, this deficiency affects the expression of MHC class I molecules. It leads to impaired presentation of intracellular antigens to CD8+ T cells, reducing the ability to respond to viral infections and cancer.
2. MHC Class II Deficiency: Also known as bare lymphocyte syndrome type II, this deficiency affects the expression of MHC class II molecules. It impairs the presentation of extracellular antigens to CD4+ T cells, leading to susceptibility to bacterial, fungal, and opportunistic infections.

Function of MHC Molecules:

MHC molecules play a critical role in immune recognition and response:

1. MHC Class I: MHC class I molecules present intracellular antigens, such as viral proteins, to CD8+ cytotoxic T cells. This process helps eliminate infected or abnormal cells.
2. MHC Class II: MHC class II molecules present extracellular antigens to CD4+ helper T cells. This interaction is crucial for orchestrating immune responses against bacteria, fungi, and other pathogens.

Clinical Presentation:

1. MHC Class I Deficiency: Individuals with MHC class I deficiency are prone to viral infections and have an increased risk of malignancies due to impaired immune surveillance against transformed cells.
2. MHC Class II Deficiency: Those with MHC class II deficiency are vulnerable to recurrent bacterial and fungal infections, and they may develop severe, chronic, or opportunistic infections.

Diagnosis and Studies:

1. Genetic Testing: Diagnosis of MHC deficiency involves genetic testing to identify mutations in genes associated with MHC class I or II molecules.
2. Functional Studies: Functional assays, such as flow cytometry, assess the expression of MHC molecules on cell surfaces and their ability to present antigens.

Treatment Considerations:

1. Infection Management: Treatment involves aggressive management of infections with appropriate antimicrobial agents.
2. Stem Cell Transplantation: In severe cases of MHC deficiency, allogeneic stem cell transplantation may be considered to replace the defective immune system with healthy donor cells.

Clinical Significance:

1. Immunodeficiency: MHC deficiency significantly impairs the immune system’s ability to recognize and respond to infections, resulting in recurrent and severe infections.
2. Autoimmunity: The absence of proper immune regulation due to MHC deficiency can lead to autoimmune disorders.

Research and Treatment Advancements:

1. Gene Therapy: Researchers are exploring gene therapy approaches to correct MHC deficiency, potentially restoring immune function.
2. Immune Reconstitution: Stem cell transplantation can offer a potential cure for severe MHC deficiency by replacing the defective immune system with healthy donor cells.

Conclusion:

MHC deficiency encompasses rare genetic disorders that impact the expression and function of MHC molecules critical for immune recognition and response. MHC class I deficiency leads to vulnerability to viral infections and malignancies, while MHC class II deficiency results in susceptibility to bacterial and fungal infections. Diagnosis involves genetic and functional testing, with treatment focusing on infection management and stem cell transplantation in severe cases.

The clinical significance of MHC deficiency lies in the increased risk of infections and autoimmune disorders. Ongoing research into gene therapy and immune reconstitution offers hope for future treatment advancements. Medical professionals must have a comprehensive understanding of MHC deficiency to diagnose, manage, and provide appropriate care for affected individuals and contribute to the ongoing research in this field.

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