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Factors Affecting Antigen Immunogenicity (影响抗原免疫原性的因素)

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Overview

1. Physicochemical & structural properties of the antigen molecule
2. Host characteristics
3. Route of antigen entry into the body

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Part I — Physicochemical & Structural Properties of the Antigen Molecule

1. Foreignness (异物性) — THE #1 REQUIREMENT for an antigen

The immune system's job is to recognize and reject foreign substances (异物).

• Its chemical structure differs from the host's own components, OR
• It was never encountered by immune cells during the embryonic period (not recognized as "self")

Three categories of foreign substances:

⚠️ High Yield: Sequestered antigens (精子, 脑组织, 眼晶状体蛋白) are physically isolated from the immune system. If released (e.g., trauma), they are treated as "foreign" and can trigger autoimmune disease.

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2. Chemical Modification Properties (化学修饰属性)

• The chemical nature and functional groups of an antigen determine its immunogenicity.
• Immune cells most commonly recognize proteins — also polysaccharides, lipids, nucleic acids.
• Ranking: Proteins > Polysaccharides > Lipids/Nucleic acids (weakest)
• Mammalian nuclear components (DNA, histones) are normally non-immunogenic in healthy cells.
  • However, after cell death/activation → DNA undergoes hypomethylation and structural changes → becomes immunogenic → can trigger autoantibodies (relevant to SLE/lupus)

⚠️ High Yield: Proteins are the most potent immunogens. Polysaccharides are moderate. Pure lipids and nucleic acids are generally poor immunogens unless modified.

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3. Physical State & Molecular Structure (物理性状与分子结构)

Molecular Weight — Critical Factor

• More epitopes (antigen-binding sites) available
• More stable molecular structure
• Harder to be degraded and cleared
• Stronger stimulation of lymphocytes → stronger immune response

Classic Examples:

• Gelatin (明胶), MW = 100 kDa: Despite its large size, it consists only of straight-chain amino acids → very weak immunogenicity
  • Add aromatic amino acids (benzene ring groups, 2% tyrosine) → immunogenicity dramatically increases
• Insulin (胰岛素), MW = only 5.7 kDa: Despite small size, contains complex aromatic amino acids → still relatively immunogenic

⚠️ High Yield: MW alone doesn't determine immunogenicity — chemical complexity (especially aromatic amino acids) matters equally.

Physical State:

• Particulate antigens (颗粒性抗原) — stronger immunogenicity
• Soluble antigens (可溶性抗原) — weaker immunogenicity
• Attaching soluble antigens to particle surfaces increases their immunogenicity (this is the principle behind some vaccine adjuvants/carriers)

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4. Spatial Conformation (空间构象)

• The 3D shape of the epitope is a key factor affecting immunogenicity.
• BCR (B cell receptor) and antibodies recognize the 3D surface shape of the antigen.
• Chemical group type, position, and spatial arrangement all significantly affect immune reactivity.

• Aminobenzene sulfonic acid → strong reaction (+++)
• Aminobenzene arsenic acid → weak reaction (+)
• Aminobenzene acetic acid → minimal (+/−)

• Meta-position aminobenzene sulfonic acid: +++
• Para-position: +/−
• Ortho-position: ++

⚠️ High Yield: A single change in the position of a chemical group on the epitope can dramatically change the strength of immune recognition. This shows that immune recognition is exquisitely specific for 3D conformation.

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5. Accessibility (易接近性)

• Defined as: how accessible the epitope is to BCR in 3D space
• Epitopes that are exposed on the surface of the antigen molecule are more easily recognized → stronger immunogenicity
• Buried or hidden epitopes are not recognized → poor immunogenicity

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Part II — Host Characteristics (宿主的特性)

1. Genetic Factors (遗传因素)

• The immune response capacity is controlled by multiple genes, especially MHC (Major Histocompatibility Complex) genes — in humans called HLA genes
• Different mice strains and different individual humans respond differently to the same antigen
• MHC determines which peptide epitopes get presented to T cells

⚠️ High Yield: MHC/HLA is the genetic controller of immune responsiveness. This explains why vaccines don't work equally in everyone.

2. Age, Sex & Health Status (年龄、性别与健康状态)

⚠️ High Yield: This explains why vaccines are less effective in the very young, elderly, pregnant women, and immunocompromised individuals.

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Part III — Route of Antigen Entry (抗原进入机体方式的影响)

1. Dose

• Too high OR too low → immune non-responsiveness (tolerance/耐受) is induced
• Optimal dose → best immune response

2. Route of Entry (ranked by immunogenicity, lowest → highest):

Oral < Intravenous (IV) < Intraperitoneal < Intramuscular < Subcutaneous < Intradermal

• Intradermal injection (皮内注射) → strongest immune response (most dendritic cells in dermis)
• Oral route → weakest systemic immune response (may induce oral tolerance)

3. Adjuvants (佐剂)

• Alum adjuvant (铝佐剂) → preferentially stimulates IgG production
• Adjuvants generally enhance and prolong immune responses

⚠️ High Yield: The route of antigen administration is clinically critical for vaccine design. Intradermal > Subcutaneous > Intramuscular for immunogenicity. Alum adjuvant promotes IgG.

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🔑 Master Summary Table — High-Yield Points

Antigen Presenting Cells (抗原提呈细胞 — APC)

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Section 1 — Concept of APCs

1. Takes up an antigen
2. Processes it into antigenic peptides
3. Loads those peptides onto MHC molecules (forming a peptide-MHC complex)
4. Displays this complex on the cell surface
5. Gets recognized by T cells → triggering an immune response

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Section 2 — Classification of APCs

Two Major Types Based on MHC Class Used:

⚠️ High Yield: MHC II → exogenous antigens → CD4⁺ T cells. MHC I → endogenous antigens → CD8⁺ T cells. This is one of the most tested concepts in immunology.

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Type 1 APCs (MHC II — presenting exogenous antigens)

(1) Professional APCs (专职性APC)

(2) Non-Professional APCs (非专职性APC)

• Do not normally express MHC II
• Can be induced to express MHC II during inflammation or by cytokines
• Much weaker antigen-processing and presenting ability
• Examples: endothelial cells, epithelial cells, fibroblasts

Type 2 APC — "Target cells" (靶细胞) presenting endogenous antigens via MHC I

• Any cell infected by an intracellular pathogen or containing mutant proteins (tumor cells)
• Presents endogenous peptides via MHC I to CD8⁺ T cells → T cell kills the target cell
• This is the broad definition of APC

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Section 3 — Professional APCs in Detail

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(一) Dendritic Cells (树突状细胞, DC)

DC = The most powerful APC in the body

1. Types of DCs (by origin):

⚠️ High Yield: DC is the ONLY APC that can directly activate naïve (virgin) T cells. Macrophages and B cells can only activate already-activated or memory T cells.

2. Maturation Stages of cDC:

Comparison Table — Immature vs. Mature DC:

⚠️ High Yield: Immature DC = expert at capturing antigen. Mature DC = expert at presenting antigen. These are inverse relationships — memorize this table.

Immature DCs by Location:

3. Functions of DCs:

1. Recognize and capture antigens → participate in innate immunity
2. Process and present antigens → initiate adaptive immunity ← (most important function)
3. Immune regulation → secrete cytokines and chemokines (e.g., IL-12 drives Th0 → Th1 differentiation)
4. Induce and maintain immune tolerance:
   • Immature DC → peripheral immune tolerance
   • Thymic DC → central immune tolerance (deletes self-reactive T cell clones via negative selection)

• Signal 1: Provides peptide-MHC complex (TCR binding)
• Signal 2: High expression of CD80, CD86, CD40 (co-stimulatory molecules)
• Signal 3: Secretes cytokines + high expression of adhesion molecules → fully initiates immune response

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(二) Macrophages (巨噬细胞, Mφ)

• Cannot directly present antigen to naïve T cells
• Instead, present antigen to activated T cells or effector T cells at sites of infection/injury
• Antigen presenting ability is significantly weaker than DC
• Key feedback loop: Macrophages activate T cells → activated T cells secrete IFN-γ → IFN-γ feeds back to further activate macrophages
• Therefore: the significance of macrophage antigen presentation is to amplify and enhance its own function

⚠️ High Yield: Mφ presents to activated/memory T cells (NOT naïve T cells). DC presents to naïve T cells. IFN-γ from T cells activates Mφ in a positive feedback loop.

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(三) B Lymphocytes (B细胞)

• B cells have no phagocytic ability
• Antigen uptake methods:
  1. Non-specific pinocytosis (minor)
  2. BCR-mediated specific uptake — BCR on the B cell surface recognizes and binds antigen → antigen is internalized → processed inside → presented as peptide-MHC II complex to CD4⁺ Th cells
• B cell APC function is especially important when antigen concentration is LOW

1. B cell BCR binds antigen → internalizes and processes it
2. Presents peptide-MHC II to CD4⁺ T helper cell
3. Activated T cell expresses CD40L → binds CD40 on B cell → provides Signal 2 to B cell
4. B cell fully activates + proliferates + differentiates into plasma cells → secretes antibodies
5. Critical for humoral immune response (especially against T-dependent antigens, TD-Ag)

⚠️ High Yield: B cell APC function happens mainly in lymph nodes. B cells present to CD4⁺ Th cells to get help for antibody production. CD40-CD40L interaction = Signal 2 for B cell activation.

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Summary Comparison — The 3 Professional APCs

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🔑 High-Yield Master Notes