MICA Human
Description
Introduction to MICA Human
MICA Human (Major Histocompatibility Complex class I-related chain A) is a critical transmembrane glycoprotein expressed in humans, primarily recognized as a ligand for the activating receptor NKG2D on immune cells such as natural killer (NK) cells, NKT cells, γδ T cells, and CD8+ β T cells . Its primary role involves triggering cytotoxic immune responses against stressed, infected, or malignant cells . Structurally, MICA shares distant homology with MHC class I molecules but lacks peptide-binding capacity and β2-microglobulin interaction .
Immune Activation and Tumor Surveillance
MICA binds NKG2D, activating cytolytic activity and cytokine production in immune cells . This mechanism is pivotal in:
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Antitumor responses: MICA-expressing tumor cells are targeted by NK cells and CD8+ T cells .
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Infection control: Induced by bacterial/viral pathogens to enhance pathogen clearance .
Immune Evasion and Autoimmunity
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Soluble MICA (sMICA): Chronic shedding downregulates NKG2D on immune cells, impairing tumor recognition .
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Autoimmune diseases: Dysregulated MICA expression may contribute to conditions like rheumatoid arthritis .
Allelic Diversity and NKG2D Binding
MICA alleles exhibit variable NKG2D binding affinities, influenced by amino acid substitutions (e.g., Met129Val) . Common alleles include:
| Allele | Frequency (European-Americans) | Frequency (African-Americans) | NKG2D Binding Affinity |
|---|---|---|---|
| 00201 | 27% | 22% | High |
| 004 | 18% | 20% | Moderate |
| 00801 | 15% | 25% | Low |
Prognostic Value in Cancers
A systematic review of 19 studies (2,588 patients) revealed :
MICAgen Mouse Model
Transgenic MICAgen mice recapitulate human MICA regulation:
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Tissue expression: Broad MICA transcripts but restricted protein expression .
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Tumor responses: Delayed growth of MICA-expressing tumors (e.g., B16F10-MICA) due to NKG2D-mediated immunity .
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Immunotolerance: No anti-MICA antibodies in tumor-bearing mice, enabling anti-MICA immunotherapy testing .
Therapeutic Antibodies
Anti-MICA antibodies (e.g., 6E1) reverse sMICA-induced immunosuppression by forming immune complexes that activate NK cells via Fc receptors . Preclinical studies highlight their potential in cancer immunotherapy .
Detection and Analytical Methods
MICA is quantified using:
Product Specs
GQWAEDVLGNKTWDRETRDLTGNGKDLRMTLAHIKDQKEGLHSLQE
IRVCEIHEDNSTRSSQHFYYDGELFLSQNLETEEWTVPQSSRAQTLAM
NVRNFLKEDAMKTKTHYHAMHADCLQELRRYLESGVVLRRTVPPMVN
VTRSEASEGNITVTCRASSFYPRNIILTWRQDGVSLSHDTQQWGDVLP
DGNGTYQTWVATRICRGEEQRFTCYMEHSGNHSTHPVPSGKVLVLQSH.
Q&A
What is MICA and what is its fundamental role in human immunology?
MICA is a member of the MHC class I chain-related protein family located on chromosome 6 within the human major histocompatibility complex, positioned between HLA-B and MICB genes. Unlike classical HLA genes, MICA does not present peptides but instead functions as a stress-induced protein that activates the NKG2D receptor found primarily on NK cells and T cell subsets. This activation promotes immune cell recognition and surveillance, particularly in the context of cellular stress responses .
MICA is widely expressed in normal human tissues, with the notable exception of the nervous system. The protein's expression is upregulated under cellular stress conditions, serving as an important signal for the immune system to identify potentially compromised cells .
How are MICA genes distributed across human populations?
Recent genotyping of more than two million individuals has revealed surprisingly high frequencies of MICA copy number variations (CNVs). Specifically, researchers have identified MICA duplications in approximately 1% of the studied population and MICA deletions in about 0.4%. These variations show significant ethnic differences, with some populations showing much higher frequencies - up to 2.8% duplications in Croatia and 9.2% deletions in Mexico .
The table below summarizes the current understanding of MICA CNV distribution:
| Population Group | MICA Duplication Frequency | MICA Deletion Frequency |
|---|---|---|
| Global Average | 1.0% | 0.4% |
| Croatia | 2.8% | Not specifically reported |
| Mexico | Not specifically reported | 9.2% |
What techniques are available for measuring MICA in human samples?
The primary quantitative method for measuring MICA in human samples is the solid-phase sandwich ELISA (enzyme-linked immunosorbent assay). This technique is designed to quantitate human MICA in serum, plasma, or cell culture medium samples and can recognize both natural and recombinant human MICA .
The principle of this method involves:
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Pre-coating wells with a target-specific antibody
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Adding samples, standards, or controls that bind to the immobilized (capture) antibody
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Forming a sandwich with the addition of a second (detector) antibody
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Adding substrate solution that reacts with the enzyme-antibody-target complex
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Measuring the signal intensity, which is directly proportional to MICA concentration
Each ELISA kit undergoes validation for criteria including sensitivity, specificity, precision, and lot-to-lot consistency to ensure reliable results .
How can researchers effectively detect MICA copy number variations?
Researchers have implemented amplicon-based genotyping approaches for detecting MICA copy number variations. The current methodology involves:
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DNA isolation from biological samples (e.g., buccal swabs)
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PCR amplification of selected exons
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Additional barcoding PCR
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Pooling and clean-up of samples
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Sequencing using platforms such as HiSeq 2500 or NovaSeq 6000
For confirming suspected copy number variations, whole gene sequencing provides more definitive results. Researchers should note that between May 2019 and October 2021, processing of 2,188,836 samples identified 22,880 samples (1%) with three copies of MICA, suggesting this variation is more common than previously recognized .
What mechanisms underlie MICA copy number variations in humans?
Targeted sequencing of more than 70 samples indicates that MICA copy number variations originate from independent nonallelic homologous recombination events. These events occur between segmental duplications upstream of MICA and MICB genes .
The mechanism appears distinct from previously identified patterns, as samples with MICA CNVs typically display normal HLA genotyping results for neighboring genes (HLA-B and MICB). This suggests these variations represent specific recombination events rather than larger chromosomal abnormalities .
How does MICA expression relate to tumor immunosurveillance?
MICA is widely expressed on many tumor types, and its interaction with the NKG2D receptor is believed to stimulate anti-tumor reactivity by T lymphocytes. This interaction represents an important mechanism in cancer immunosurveillance .
While MICA mRNA is widely expressed in normal tissues, the regulation of protein expression appears to be complex. The widespread expression of MICA suggests that protein expression may be just one component of the anti-tumor activity of the immune system .
Research indicates that understanding the factors controlling MICA expression and its recognition by immune cells could provide insights into novel cancer immunotherapy approaches. Variations in MICA copy number may also influence cancer susceptibility and response to immunotherapy, though more research is needed to establish these relationships .
What considerations are important when designing human subjects research involving MICA?
When designing human subjects research related to MICA, researchers must obtain proper training and certification. For example, institutions like MICA (Maryland Institute College of Art) require researchers to complete Human Subjects Research Training through vendors like CITI. The certification is valid for three years and must be included with IRB applications .
Key training components typically include:
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Understanding ethical principles in human subjects research
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Protocol design considerations
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Informed consent procedures
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Risk assessment and minimization
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Privacy and confidentiality protections
The training course typically consists of approximately 12 modules requiring about 3 hours to complete, with assessments after each module requiring an average score of 80% for certification .
How should researchers approach the analysis of MICA expression in diverse populations?
When analyzing MICA expression across diverse populations, researchers should account for the high frequency of copy number variations that differ significantly between ethnic groups. Study designs should incorporate:
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Stratification of data by ethnic background
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Screening for MICA copy number variations (duplications and deletions)
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Consideration of linkage disequilibrium with HLA-B and other MHC genes
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Use of appropriate sequencing technologies to detect variations
Given that MICA duplications can reach frequencies of 2.8% in some populations and deletions up to 9.2% in others, failure to account for these variations could significantly impact research findings and interpretations .
How should researchers interpret contradictory data regarding MICA expression and function?
When encountering contradictory data regarding MICA expression and function, researchers should consider:
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Tissue-specific expression patterns - MICA is widely expressed but may have tissue-specific regulation
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Stress-induced upregulation - experimental conditions may influence expression levels
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Copy number variations - subjects with duplications or deletions may show atypical expression patterns
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Technical limitations of detection methods - different assays may yield different results
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Post-transcriptional regulation - mRNA levels may not correlate with protein expression
Researchers should thoroughly document experimental conditions and subject characteristics, including potential genetic variations that might explain discrepancies in observed MICA expression or function.
What statistical approaches are recommended for analyzing MICA copy number variation data?
When analyzing MICA copy number variation data, researchers should consider:
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Hardy-Weinberg equilibrium testing to verify population genetics assumptions
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Stratification by ethnic background to account for population differences
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Linkage disequilibrium analysis with neighboring genes like HLA-B
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Case-control comparison methodologies for disease association studies
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Multiple testing correction given the complex genetic architecture of the MHC region
Given the high frequency of these variations in certain populations, power calculations should account for variable prevalence rates when designing studies that investigate associations between MICA CNVs and disease outcomes .
Product Science Overview
The Major Histocompatibility Complex (MHC) class I chain-related gene A (MICA) is a member of the MHC class I family, which plays a crucial role in the immune system. MICA is encoded within the human leukocyte antigen (HLA) class I region on chromosome 6 . Unlike classical HLA class I molecules, MICA does not present peptides to T cells but instead interacts with natural killer (NK) cells and certain subsets of T cells through the NKG2D receptor .
MICA is a polymorphic protein, meaning it has multiple variants within the population. It is composed of an α chain that is similar to classical HLA class I molecules but lacks the β2-microglobulin association . MICA is expressed on the surface of various cell types, including epithelial cells, fibroblasts, and endothelial cells, particularly under conditions of cellular stress, damage, or transformation .
The primary function of MICA is to act as a “stress-induced ligand” for the NKG2D receptor on NK cells and certain T cells . When cells are stressed, damaged, or transformed (e.g., during infection or tumorigenesis), MICA expression is upregulated. This upregulation serves as a signal for NK cells to target and destroy the affected cells, thus playing a critical role in immune surveillance and the elimination of potentially harmful cells .
MICA has been extensively studied in the context of organ transplantation, cancer, and autoimmune diseases. In transplantation, the presence of antibodies against MICA has been associated with graft rejection and reduced graft survival . In cancer, MICA expression on tumor cells can make them more susceptible to NK cell-mediated lysis, making it a potential target for immunotherapy . Additionally, soluble forms of MICA (sMICA) can be released into the bloodstream, where they may interfere with NK cell function and contribute to immune evasion by tumors .
Recombinant MICA (rMICA) refers to the MICA protein produced through recombinant DNA technology. This involves inserting the MICA gene into an expression system, such as bacteria or mammalian cells, to produce the protein in large quantities. Recombinant MICA is used in research to study its structure, function, and interactions with other molecules. It is also being explored as a potential therapeutic agent in cancer immunotherapy .
