Innate Immunology notes PDF

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11.INNATE IMMUNOLOGY1. PHAGOCYTOSISThe internalization of particulate matter by a process of engulfment, eventually forming a vesical (phagosome) containing the ingested material A. Phagocytes i. Macrophages ii. Granulocytes: neutrophils, eosinophils, and basophils Primary function is to engulf and ...

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11.10.2018

INNATE IMMUNOLOGY 1. PHAGOCYTOSIS The internalization of particulate matter by a process of engulfment, eventually forming a vesical (phagosome) containing the ingested material A. Phagocytes i.

Macrophages

ii.

Granulocytes: neutrophils, eosinophils, and basophils - Primary function is to engulf and destroy pathogen

iii.

Immature dendritic cells - Primary function is to generate peptide antigen for presentation to T cells and activation of adaptive immunity

iv.

Some microbes (esp. those with capsules) are difficult to phagocytose.

v.

Opsonization is the coating of microbe with proteins, such as antibodies or complement, that facilitate phagocytosis.

vi.

Acute phase proteins produced by the liver ex) C reactive protein (CRP) will bind to phosphocholine on bacteria and act as an opsonin

vii.

These proteins are recognized by specific receptors on the surface of the phagocyte.

2. RECRUITMENT OF EFFECTOR CELLS Recruitment of effector to the site of infection is an important step in control of infection.

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3. NEUTROPHIL RECRUITMENT

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i.

Activation by inflammatory cytokines ex (TNFα, IL-1) induces expression of Eselection on the endothelium.

ii.

Weak interactions with carbohydrate ligands on the neutrophils, slows the movement, causing rolling.

iii.

Chemokines induce conformation changes in integrins ex (LFA-1), allowing the leukocyte to adhere tightly to the endothelial cells via interactions with their ligands ex (ICAM-1, also upregulated by inflammatory cytokines like TNF), cross the blood vessel walls (extravasation).

iv.

Chemokines direct the migration of the cell along its concentration gradient.

4. MONOCYTE RECRUITMENT CCL2 and CCL7 both bind to CCR2 chemokine receptor and recruit monocytes

5. NATURAL KILLER CELLS 5

NK cells are innate lymphoid cells. In addition to cytokine production, they can kill cell i.

Through the release of cytotoxic granules (similar to cytotoxic T cells) containing perforin and granzyme.

ii.

Induction of apoptosis via Fas, and TRAIL-R engagement.

iii.

NK cells can become activated through the ligation of activating receptors e.g. NKG2D

iv.

NK cells express an Fc receptor (CD16) allowing antibody-dependent cell cytotoxicity (ADCC)

v.

NK cells may become activated by the absence of a ligand. A resting NK cell is kept in check by a balance of constitutive inhibitory signals AND constitutive activating signal. An important source of the inhibitory signals are MHC class I molecules (HLA class I). Loss or downregulation of HLA class I (as in viral infection or cancer), leads to activation via a process called “missing self”.

vi.

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NKG2D ligands (e.g. MICA, MICB, ULBPs) are upregulated on cells in response to cellular and metabolic stress. See increases with intracellular bacterial and viral infections, and in cancer.

6. ANTIGEN PROCESSING AND PRESENTATION

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7. DENDRITIC CELLS Because of their central role in processing and presenting antigen, DCs are consider as professional antigen presenting cells (APCs). Macrophages and B cells also act as APCs.

8. ANTIGEN PRESENTATION 8

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i.

B cell can recognize unprocessed antigen.

ii.

T cell require antigen to be processed into peptide fragments and presented in MHC (HLA) Class 1 or Class 2 molecules.

9. MHC CLASS 1 Presentation of cytosolic peptide on MHC class 1 molecules to CD8 + Cytotoxic T cells i.

Assembly of the MHC 1 molecule happens in the endoplasmic reticulum with the help of specific chaperone molecules which ensure correct folding. Once the molecule is in the correct conformation a high affinity peptide (8-10 amino acids in length) is loaded into the peptide binding groove.

ii.

There are 3 classical MHC class 1 genes in humans, encoded on chromosome 6. (HLA-A, HLA-B and HLA-C).

iii.

They are the most polymorphic genes in the human genome. Variants of each gene denoted by number e.g. HLA-B*0701, HLA-B*2705, and differ in their peptidebinding characteristics.

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MHC CLASS 2 Presentation of intravascular peptide on MHC class 2 molecules to CD4 + Helper T cells i.

Assembly of the MHC 2 molecule happens in the endoplasmic reticulum, but the peptide binding groove is protected from premature binding of peptide – these molecules will present peptide that is held within endocytic vesicles.

ii.

Extracellular peptide can be presented by dendritic cells, macrophages or in this case B cells e.g. Antigen Presenting Cells (APCs). The antigen binds to the BCR which is internalized rather than the antigen being engulfed by a phagocyte. In both cases however the antigen is internalized into an endocytic vesicle.

iii.

Purpose: DC: To activate CD4 T cell B cell and Macrophage: To receive help from CD4 T cells

iv.

There are six main MHC class 2 genes in humans: HLA-DPA1, HLA-DPB1, HLADQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1 They are very polymorphic genes.

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