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BSC SEM 1 UNIT 8 APPLIED BIOCHEMISTRY

UNIT 8 Immunochemistry

What is Immunochemistry?

Definition:
Immunochemistry is the branch of biochemistry that studies the chemical properties of immune reactions, particularly antigen-antibody interactions at a molecular level. It combines principles from immunology and biochemistry to explore and utilize the interactions between antigens and antibodies for diagnostic, therapeutic, and research purposes.


Key Components in Immunochemistry:

1. Antigens (Ag):

  • Definition: Substances (proteins, polysaccharides, lipids, nucleic acids) that provoke an immune response.
  • Types:
    • Exogenous (foreign antigens)
    • Endogenous (from body’s own tissues, sometimes auto-antigens)
  • Epitope: Specific part of antigen recognized by antibodies.

2. Antibodies (Immunoglobulins, Ig):

  • Structure: Y-shaped proteins produced by plasma cells (activated B cells).
  • Structure:
    • Two heavy chains and two light chains.
    • Variable region (Fab region) binds specifically to antigen.
    • Constant region (Fc region) mediates effector functions.
  • Types: IgG, IgM, IgA, IgE, IgD.

2. Antigen-Antibody Interaction:

  • Highly specific binding occurs through non-covalent interactions:
    • Hydrogen bonds, electrostatic interactions, hydrophobic interactions, Van der Waals forces.
  • Affinity: Strength of interaction between a single antigenic determinant and a single antibody binding site.
  • Avidity: Overall binding strength between antibody and antigen (multiple binding sites).

Biochemical Principles in Immunochemistry:

1. Specificity:

  • Antibody-antigen interactions are highly specific, relying on complementary shapes and biochemical interactions (hydrogen bonds, electrostatic interactions, hydrophobic interactions).

2. Affinity and Kinetics:

  • Affinity: Measured by the equilibrium dissociation constant (Kd).
  • Strong affinity: Leads to stronger and longer-lasting immune responses.

2. Non-Covalent Interactions:

  • Hydrogen bonds, ionic interactions, Van der Waals forces, and hydrophobic interactions facilitate antibody-antigen binding.

3. Epitope (Antigenic Determinant):

  • The precise region on the antigen recognized by antibodies.

Methods and Techniques in Immunochemistry:

1. Immunoassays:

  • ELISA (Enzyme-linked Immunosorbent Assay):
    • Detects antigens or antibodies using enzyme-labeled antibodies.
    • Used for disease diagnosis, hormone measurement, drug screening, etc.

2. Immunofluorescence (IF):

  • Antibodies tagged with fluorescent molecules detect antigens in tissues or cells under a fluorescence microscope.
    • Direct IF: Fluorophore-labeled antibody binds directly to antigen.
    • Indirect IF: Secondary antibody labeled with fluorophore detects primary antibody-antigen complex.

4. Immunohistochemistry (IHC):

  • Uses antibodies tagged with enzymes or dyes to visualize antigens in tissue sections microscopically.

5. Enzyme-linked Immunosorbent Assay (ELISA):

  • Quantitative assay using antibodies linked with enzymes to measure antigens or antibodies in biological samples.
  • Commonly used enzymes: Horseradish Peroxidase (HRP), Alkaline Phosphatase (ALP).

4. Western Blotting:

  • Technique for detecting specific proteins using antibodies.
  • Steps include:
    • Protein separation by electrophoresis (SDS-PAGE).
    • Transfer proteins onto membranes.
    • Incubate membrane with specific antibodies for detection.

5. Immunohistochemistry (IHC):

  • Localization of antigens within tissue sections using enzyme-linked antibodies.
  • Visualization by enzyme-substrate reactions producing colored precipitates.

5. Enzyme-Linked Immunosorbent Assay (ELISA):

  • Quantitative immunoassay for antigen or antibody detection.
  • Types:
    • Direct ELISA
    • Indirect ELISA
    • Sandwich ELISA
    • Competitive ELISA

Clinical and Diagnostic Applications:

  • Diagnosing infectious diseases (HIV, Hepatitis).
  • Allergy testing (IgE detection).
  • Cancer markers identification.
  • Autoimmune disorders detection (e.g., rheumatoid arthritis, systemic lupus erythematosus).

Immunochemical Reagents:

  • Primary antibodies: Bind directly to antigen.
  • Secondary antibodies: Bind to primary antibodies; conjugated with detection molecules (enzymes, fluorophores).
  • Conjugates: Antibodies linked chemically to enzymes or fluorescent dyes for visualization.

Biochemical Importance in Nursing and Medical Field:

  • Disease Diagnosis: Immunochemistry techniques (ELISA, IF, western blotting) used in diagnosis of infectious diseases, autoimmune disorders, and cancer biomarkers.
  • Therapeutic Monitoring: Measuring drug concentrations, hormones, tumor markers.
  • Research Applications: Studying pathogenesis, drug discovery, and vaccine development.

Clinical Applications:

  • Immunohistochemistry: Identification of tumor markers (e.g., HER2, ER, PR in breast cancer).
  • Western Blotting: Confirmatory test in HIV diagnosis.
  • ELISA: Screening tests for infectious diseases (HIV, Hepatitis).

Applications in Nursing and Health Sciences:

  • Understanding disease pathology and management.
  • Drug monitoring (therapeutic drug monitoring).
  • Vaccine evaluation and immunogenicity testing.
  • Research on immune system disorders.

Future Perspectives in Immunochemistry:

  • Advanced biosensor technologies.
  • Development of monoclonal antibodies and targeted immunotherapies.
  • Personalized medicine based on immunochemical markers.

Immunochemistry: Structure, Functions, and Biochemistry of Immunoglobulins (Antibodies)

What are Immunoglobulins?

Immunoglobulins (Ig), commonly known as antibodies, are specialized glycoproteins produced by plasma cells (activated B-lymphocytes). They play a critical role in the immune response by recognizing and neutralizing pathogens such as bacteria and viruses.


Biochemical Structure of Immunoglobulins

Each immunoglobulin molecule is composed of four polypeptide chains:

  • Two Heavy (H) chains: (~50-75 kDa each)
  • Two Light chains: (Kappa κ or Lambda λ; about 25 kDa each)

The heavy and light chains are linked by disulfide bonds.

Basic Structure:

  • Y-shaped molecule:
    • Two identical antigen-binding sites (Fab regions).
    • A constant region (Fc region) responsible for biological functions.

Domains:

  • Variable (V) region: Contains antigen-binding sites; varies between antibodies.
  • Constant region (C region): Responsible for mediating biological functions.

Heavy Chains (5 types/classes):

Each immunoglobulin type is named according to the heavy chain type:

ImmunoglobulinHeavy ChainSubtypes
IgGGamma (γ)γ1, γ2, γ3, γ4
IgMMu (μ)
IgAAlpha (α)α1, α2
IgDDelta (δ)
IgEEpsilon (ε)

Classes and Functions of Immunoglobulins:

1. IgG (Gamma globulin)

  • Structure: Monomer (single Y-shaped unit)
  • Concentration: Most abundant antibody in plasma (~75% of serum antibodies).
  • Function:
    • Main antibody in secondary immune response.
    • Opsonization (enhances phagocytosis).
    • Neutralization of toxins and viruses.
    • Crosses placenta providing passive immunity to the fetus.
    • Activates complement system.

2. IgM (Macroglobulin)

  • Structure: Pentamer (5 Y-shaped units linked by J-chain)
  • Concentration: ~10% of serum antibodies.
  • Function:
    • Primary immune response antibody.
    • First antibody produced during infection.
    • Strongly activates complement system.
    • Indicator of recent infection.

3. IgA (Secretory antibody)

  • Structure:
    • Monomer in serum, Dimer in secretions (tears, saliva, breast milk, mucus).
    • Secretory component for mucosal protection.
  • Function:
    • Protects mucosal surfaces (GI tract, respiratory tract, urogenital tract).
    • Provides immunity in secretions (breast milk, saliva, tears).
    • Prevents attachment of pathogens to mucosal surfaces.

4. IgE (Reaginic antibody)

  • Structure: Monomer
  • Function:
    • Important in allergic reactions and parasitic infections.
    • Binds strongly to mast cells and basophils.
    • Releases histamine upon antigen binding, causing inflammatory response (e.g., asthma, anaphylaxis).

5. IgD

  • Structure: Monomer, low concentration in plasma
  • Function:
    • Acts primarily as an antigen receptor on naive B cells.
    • Little known about specific functions.
    • Possibly involved in B-cell differentiation.

Biochemical Features of Immunoglobulins:

Glycoprotein nature:

  • Composed of proteins with carbohydrate side chains (glycosylation).
  • Glycosylation stabilizes antibodies and modulates effector functions.

Disulfide bonds:

  • Provide structural stability and flexibility.
  • Essential for antigen-binding specificity and affinity.

Antigen Binding:

  • Highly specific due to complementary shape and charges.
  • Non-covalent bonds: hydrogen bonding, ionic bonds, Van der Waals forces, hydrophobic interactions.

Variable and Constant Regions:

  • Variable region (V-region): Unique amino acid sequences determine specificity for antigen binding.
  • Constant region (C-region): Determines antibody class and effector functions (complement binding, binding to immune cells).

Clinical and Diagnostic Applications of Immunoglobulins:

Diagnostic uses:

  • Serological tests: ELISA, Western blotting, Immunofluorescence assays.
  • Identification of infections: Detection of specific antibodies (IgG, IgM) helps diagnose infections.
  • Autoimmune disorders: Detection of autoantibodies.

Laboratory Techniques in Immunochemistry involving Immunoglobulins:

  • Immunofluorescence
  • Western Blotting
  • ELISA (Enzyme-Linked Immunosorbent Assay)
  • Immunohistochemistry
  • Flow cytometry

Summary Table of Immunoglobulin Classes:

FeatureIgGIgMIgAIgEIgD
StructureMonomerPentamerDimer/MonomerMonomerMonomer
Molecular Weight150 kDa900 kDa320 kDa200 kDa180 kDa
Half-life21 days5 days6 days2 days2-3 days
Serum Conc.Highest (~75%)~10%~10-15%Trace amounts<1%

Enzyme-Linked Immunosorbent Assay (ELISA)

Introduction

  • ELISA is a biochemical technique used widely in immunochemistry to detect and quantify antigens or antibodies in a sample.
  • It combines the specificity of antibodies with the catalytic efficiency of enzymes for sensitive detection.

Basic Principle of ELISA

ELISA is based on antigen-antibody interactions and enzyme-substrate reactions:

  • Specific antibodies bind to their respective antigens.
  • Enzyme-labeled antibodies produce color reactions that can be quantitatively measured.

Key Components in ELISA

  1. Antigen: Target molecule of detection (protein, hormone, pathogen).
  2. Antibody: Binds specifically to antigens; can be primary or secondary.
  3. Enzyme conjugate: Antibody linked to enzyme (e.g., Horseradish peroxidase [HRP], Alkaline phosphatase [ALP]).
  4. Substrate (chromogen): Chemical that reacts with enzyme to produce color.
    • Common substrates: TMB (HRP), PNPP (ALP substrate).

Types of ELISA:

| Type | Detection Target | Sensitivity | Key Features | |————————|——————|—————————-| | Direct ELISA | Antigen | Simple, rapid but less sensitive | | Indirect ELISA | Antibody | Highly sensitive; common for screening | | Sandwich ELISA | Antigen | Highest specificity and sensitivity | | Competitive ELISA | Antigen/Antibody | Ideal for small molecules; highly sensitive |


Detailed Steps in ELISA Technique

ELISA is typically performed in microtiter plates (96 wells):

  1. Coating:
    • Antigen or antibody immobilized onto microplate surface.
  2. Blocking:
    • Unoccupied binding sites are blocked with proteins (e.g., bovine serum albumin [BSA]) to prevent nonspecific binding.
  3. Sample Addition:
    • Add the biological sample (e.g., serum, plasma, urine) containing antigen or antibody.
  4. Addition of Detection Antibody:
    • Enzyme-conjugated antibody binds specifically to the antigen-antibody complex.
  5. Washing Steps:
    • Wash away unbound materials to ensure specificity.
  6. Addition of Substrate:
    • Enzyme reacts with substrate, producing a measurable signal (colorimetric or fluorescent).
  7. Measurement:
    • Quantify the reaction product (color intensity) using spectrophotometry.

Enzymes commonly used in ELISA

EnzymeSubstrateProduct Appearance
Horseradish peroxidase (HRP)TMB (Tetramethylbenzidine), OPDBlue (turns yellow after stopping reaction)
Alkaline phosphatase (ALP)p-Nitrophenyl phosphate (pNPP)Yellow

Applications of ELISA in Biochemistry & Clinical Practice

1. Diagnostic Applications

  • Infectious diseases: Detection of antibodies or antigens (e.g., HIV, Hepatitis, COVID-19).
  • Hormone assays: Measurement of hormones like TSH, LH, Insulin, HCG.
  • Autoimmune disorders: Detection of autoantibodies (e.g., rheumatoid factor, ANA).
  • Allergy testing: Quantification of IgE antibodies specific to allergens.

2. Research Applications

  • Quantitative protein analysis.
  • Cytokine detection in inflammation research.
  • Analysis of biomarkers for research and drug development.

3. Pharmaceutical Industry

  • Testing drug efficacy by measuring specific biomarkers.
  • Monitoring therapeutic antibody levels in patients.

Advantages of ELISA

  • Highly specific and sensitive.
  • Quantitative analysis possible.
  • Can be automated for high-throughput analysis.
  • Versatile application for many biological analytes.

Limitations of ELISA

  • Potential for cross-reactivity or nonspecific binding.
  • False-positive/negative results possible.
  • Requires quality antibodies and careful standardization.

Troubleshooting Common Problems in ELISA

ProblemPossible ReasonSolution
High backgroundNon-specific bindingImprove blocking step
Weak signalsLow antigen/antibody concentrationIncrease sample concentration
No color developmentIncorrect enzyme/substrate pairingEnsure enzyme-substrate compatibility
Variable resultsPipetting error, incubation variabilityStandardize procedure & calibrate equipment

Biochemical Considerations in ELISA

  • Specificity: Antigen-antibody interactions due to complementary molecular shapes and chemical interactions.
  • Affinity and avidity: Determine effectiveness of antigen-antibody binding.
  • Enzyme activity: Influenced by optimal pH, temperature, incubation time.

Applications in Nursing and Health Sciences

  • Early disease detection and patient monitoring.
  • Hormonal imbalances and reproductive health testing.
  • Community-level epidemiological surveillance.
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