L 4 Phagocytosis and Antigen

Phagocytosis is described as "cell eating", a biologically essential process where cells bind, ingest, or internalize foreign materials or dead host cells to destroy them.
All nucleated cells have some capability to perform phagocytosis, which is critical for immune responses and homeostasis.

Compare and contrast types of professional phagocytes, their functions, characteristics, and mechanisms.
Differentiate endocytosis and phagocytosis.
Understand steps of phagocytosis and the enzymes/receptors involved.
Compare the mechanisms of microbe destruction via oxygen-dependent, oxygen-independent, and nitric oxide pathways.
Learn about regulatory processes affecting phagocyte activation (both positive and negative).
Describe HLA molecules: their inheritance patterns, structures, and roles in the immune response.
Explain the two major pathways of antigen processing and presentation, and the result of antigen presentation.
Identify cell types activated by HLA class I and HLA class II molecules as well as corresponding peptides.

Definition: Phagocytes that primarily perform the process of phagocytosis.
Types:
- Neutrophils
- Comprise 60% of peripheral blood leukocytes.
- First leukocyte type to migrate to infection sites.
- Effective in phagocytosing and killing bacteria.
- Can kill intracellularly or extracellularly but cannot renew lysosomes, leading to short lifespans (typically die after ingested few microbes).
- Abundant in pus from wounds.
- Monocytes/Macrophages
- Monocytes represent 5-7% of leukocytes in blood.
- Differentiate into macrophages in tissues, adopting different names based on their environments.
- Longer lifespan (2-4 months) than neutrophils.
- Capable of antigen processing and presentation to T lymphocytes.
- Examples include microglial cells (brain), Kupffer cells (liver), alveolar macrophages (lung), and peritoneal macrophages.
- Dendritic Cells
- Predominantly located at potential pathogen entry sites (skin, GI tract).
- Named for their dendrites, which help engulf pathogens.
- Migrate to lymph nodes to present antigens to T cells.

Phagocytes that can perform some aspects of phagocytosis but have additional functions (e.g., basophils, eosinophils).
Focus of the discussion will primarily be on professional phagocytes.

**Endocytosis: ** Receptor-mediated uptake of soluble molecules.
**Phagocytosis: ** Specific ingestion of solid insoluble particles by phagocytic cells.

The process varies slightly in different organisms but typically involves the following steps:
1. Recognition and attachment of microbes
2. Ingestion of microbes and other material
3. Destruction of ingested microbes or products
4. Secretion of effector molecules

Defined as molecules that enhance the attractiveness of microbes to phagocytes when bound to their surfaces (e.g., C3b from the complement pathway, IgG).
Opsonins facilitate the tight binding and ingestion of pathogens by phagocytic cells.

Some microorganisms produce hydrophilic capsules that hinder phagocyte encirclement and ingestion, acting as virulence factors.
In these scenarios, opsonin presence becomes vital for successful phagocytosis.

Once attached, the microbe is engulfed by extensions of the cytoplasm and cell membrane known as pseudopodia.
This engulfs the microbe into a vesicle called a phagosome, which initiates phagocyte activation leading to: increased cell size, more robust phagocytosis, and production of destructive molecules.

The phagosome fuses with lysosomes forming a phagolysosome.
Within the phagolysosome, several products are released to attack and destroy the pathogen, including those generated during an oxidative burst.

The oxidative burst can produce superoxides (O₂⁻), hydroxyl radicals (OH•), and hypochlorite (chlorine bleach).
Implications for health include diseases like Chronic Granulomatous Disease, where enzymatic defects prevent effective killing of pathogens, leading to significant immunological challenges (e.g., granulomatous lesions).

Activated phagocytes secrete various molecules not only to kill pathogens but also to modulate the immune response, including:
- Chemokines (e.g., IL-8), essential for recruiting additional immune cells.
- Cytokines to activate infiltrating cells, including nitric oxide as a signaling molecule.

Phagocytes can become more efficient in pathogen recognition and elimination through:
- Stimulation of Pattern Recognition Receptors (PRRs).
- Engagement with Complement and Fc receptors.
- Release of cytokines like IFN-gamma boosts monocyte differentiation into macrophages.

After pathogen destruction, nucleic acids and amino acids can be reused by the phagocyte to generate peptide fragments for presentation to T lymphocytes.
Antigens are processed either exogenously via phagocytosis for HLA class II or endogenously for HLA class I.

HLA molecules are genetically unique identifiers, allowing distinction of self from non-self, encoded by the Major Histocompatibility Complex (MHC) on Chromosome 6.
Types of HLA molecules:
- Class I: HLA-A, HLA-B, HLA-C (present endogenous antigens).
- Class II: HLA-DP, HLA-DQ, HLA-DR (present exogenous antigens).

HLA Class I usually binds peptides 8-10 amino acids long with a CD8 binding site.
HLA Class II binds peptides 12-20 amino acids long with a CD4 binding site.

HLA Class II molecules enter the exocytic pathway with the invariant chain, fusing with phagolysosomes, degradation occurs, and peptide binding ensues to present on the cell surface.

HLA Class I forms in the ER, with proteins cytoplasmically degraded into peptides through the ubiquitin-proteosome pathway, loading peptides into the HLA Class I, which moves to the cell surface for presentation.

Cells that express HLA Class II can process and present antigen to CD4+ T helper cells, comprising primarily dendritic cells, epithelial cells, and B cells.
Cells that interact with HLA Class I can influence CD8+ T cell responses, typically stemming from nearly all nucleated cells through endogenous processing.

Overall, understanding these intricate processes, from phagocyte activation to the mechanisms of antigen presentation, reveals the complexities of the immune system and its ability to recognize and combat pathogens effectively.