Basic concepts, immunity and inflammation

Inflammation is an observable alteration in the tissues, with changes in vascular permeability and dilation. Leukocytes, the white blood cells, control all three stages of inflammation.
3 Stages of Inflammation are:

1.Immediate

2.Acute

3.Chronic

 Cardinal Signs of Inflammation:

Erythema

Oedema

Heat

Pain

Loss of function

• Immediate inflammation: main cell Resident Leukocytes*.
• Acute Inflammation: main cell is neutrophil.
• Chronic inflammation: main cell is lymphocyte and macrophage.

*Resident Leukocytes are:

• mast cells
• peripheral dendritic cells
• dermal dendrocytes  ( histiocytes)

Cells of Immunity And Inflammation

1 Mast Cells

• Immediate inflammation
• receptors for IgE and IgG
• Express toll like receptors
• Contain lysosomes
• Cause anaphylaxis

2 Dermal Dendrocytes

•  Also called Histiocytes
• Cause immediate inflammation
• Collagen associated dendritic cells of myeloid origin
• Express MHC class II molecules
• Express matrix metalloproteinases and cause periodontal tissue destruction

3 Peripheral Dendritic cells

• They are leukocytes with cytoplasmic projections or dentrites
• Langerhans cells are dendritic cells
• Ingest antigen and transfer to lymph nodes

4 Neutrophils

• Phagocytic leukocytes
• Differentiate in the bone marrow(14 days)
• Also called Polymorphonuclear Leukocytes
• Predominant leukocyte
• 2/3rd of the blood leukocyte
• 4000-8000 cells /mm3 
• Receptors for IgG

5 Monocytes/ macrophages

• Phagocytic leukocyte
• Monocytes differentiate in the tissues
• Monocytes are macrophages when they leave the blood
• 22 micrometers
• Present antigen to T cells
• Macrophages and Lymphocytes orchestrate the chronic immune response

6 Lymphocytes

They are of 3 types:

1.T cells

2.B cells

3.Natural Killer cells

1. T cells

•  Inactive in the blood
•  Small( 8-10 micrometer)
• Major histocompatibility complex
• Recognise T cell antigen receptor
• Two types: CD4+ T cells and CD8+ T cells

2. B cells

• Control extracelleular antigens such as bacteria, fungal, yeast and virions.
• 8-10 micrometer.
• Express IgM
•  After antigen exposure B cells differentiate to plasma cells
• B cells also form memory B cells in the presence of T cells, which after secondary antigen exposure convert to plasma cells.

3 Natural Killer Cells

• Kill tumor and virally affected cells
• Have killer inhibitory receptors and killer activating receptors
• Largest of all leukocytes( 15micrometer ).
• Recognize antigens associated with MHC class I molecules.

Complement (C)

• Has 30 membrane associated cell receptors and soluble serum glycoproteins
• Soluble component is 5%.
• C3 is the most important.
• Enables endothelium and leukocytes to recognize and bind foreign antigen

Transendothelial Migration

• It is the interaction between the leukocyte and endothelium to exit blood and enter tissues.
• Inflammation occurs due to interaction between complement, resident leukocytes and recruited inflammatory leukocytes.
• Neutrophils and monocytes spend less than 12 hrs in blood.
• B & T cells :30 mins(Lymphyocytic recirculation: these cells require influence of lymphoid organs. They exit the blood, enter lymphatics and lymphoid organs and then again enter the blood)

Steps in endothelial migration

Step 1: Rolling

• L-selectin is expressed(non enzymatic carbohydrate binding protein).
• Leukocytes are the main cells.

Step 2: Insult to the epithelium

Step 3:Signalling the endothelium

• Inflammatory signals( Interleukin -1beta , TNF-alpha) from mast cells in tissues.
• Mast cells recruit neutrophils against bacteria and respond to anaphylatoxins such as C3a and C5a.

Step 4: Increased rolling

•  IL-1beta, TNF-alpha and C5a stimulate endothelial cells to express P-selectin and E-selectin

Step 5: Signal for rolling arrest

• Chemokines are signals for leukocytes to exit blood
• Chemokines are signals for rolling arrest.

Step 6: Strong Adhesion

• L-selectin shed
• LFA-1 expressed
• LFA interacts with ICAM-2 on the endothelium.

Step 7: Zipper

• CD31 is the platelet endothelial cell adhesion molecule.
• CD31 is a 130 kD transmembrane glycoprotein present at the intercellular borders of endothelial cells and leukocytes.
• It is a homophilic molecule.
• CD31 on endothelium binds to CD31 on leukocytes and guides them to the boundaries between endothelial cells.
• This zipper effect minimizes the leakage of fluid.

Leukocyte Functions

1 Chemotaxis

• It is the migration of leukocyte to the site of insult.
• Receptors for chemotaxis are G-protein coupled family
• Chemotaxins derived from bacteria are: formyl methionyl peptides.

2 Phagocytosis

• These cells ingest particles of a size visible under light microscope.
• Neutrophils and macrophages are involved
• Phagosome is containment of pathogen in a membrane delimited structure.
• Opsonization is coating of pathogen with ligands
• There are two types of killings: 

1. Oxidative mechanism

•           It occurs in the presence of oxygen
•           The mechanism is oxidation -reduction potential which is -160mv(at or above).
•           Neutrophils form superoxide anion using NADPH oxidase system
•           Superoxide anion forms hydrogen peroxide.
•           Hydrogen Peroxide is s substrate for myeloperoxidase.
•           In the presence of myeloperoxidase, hydrogen peroxidase with chloride ions forms                      hypochlorous acid, which is an antimicrobial agent.
•           Deficiencies of NADPH causes chronic granulomatous disease.

   2.  Non Oxidative Killing

•          Phagosome-Lysosome fusion happens which is called phagolysosome.
•          There are two types of lysosomes in neutrophils:      
•             Specific Granules: extracellular and intraphagolysosomal secretion.         
•              Azurophil granules: intraphagolysosomal secretion
•          Specific granules have lysozyme(bactericidal and fungicidal) and lactoferrin(bacteriostatic  compound).
•          Non oxidative killing mechanism is important in periodontal diseases because of the highly anerobic condition of the subgingival environment.

3 Antigen Processing and presentation.

• MHC is present on the locus of the short arm of the chromosome 6.
• MHC encodes molecules including Class I, II and III which are involved in antigen uptake , processing and presentation.
• MHC class I presents intracellular antigens to CD8+ T cells and NK cells
• MHC class III include complement factors B, C2 and C4.
• Antigen presenting cells present antigens from extracellular sources.
• Antigen presenting cells are peripheral DC's , monocyte derivatives and B cells.
• APCs present antigen to CD4+ T cells in association with MHC class III.
• MHC exhibit pleomorphism.
• MHC are significant in transplantation.
• Co-stimulation (second signal): reaffirms T cell has recognised an antigen.

       Functions of Co-stimulation:

1. Makes T cells resistant to apoptosis.
2. upregulates growth factor receptors.
3. Decreased amount of time needed to trigger T cells( amplification).

• Toll (receptor molecule ) first identified in fruit flies.
• Toll like receptors in humans are stimulated by bacterial components like LPS.

Specific Immune Responses

• In protracted chronic inflammation.
• Requires lymphocytes, which uses two types of receptors : the B cell antigen receptor and the T cell antigen receptor.
• Steps:

1. Clonal selection: selection of lymphocytes that bear receptors(BCR/TCR) recognizing specific antigen.
2. Clonal expansion: proliferation of those lymphocytes.
3. Clonal contraction: death of effector lymphocytes.
4. Memory: maintainance of specific clone cells that bear receptors.

T cell responses

• T cell interacts with APC.
• T cell antigen recognition is a function of TCR.
• T cells express 3000-50,000 TCRs on the surface.
• MHC class I and II present antigen to T cells.
• CD-1 presents antigen to NK cells.
• CD3 transductory apparatus activates TCR.
• CD8 and CD4 are T cell co receptors.
• Scanning: Time dependent interaction of TCR with antigen.
• Scanning that triggers T cell activation is serial triggering.
• Immunophilins diminish action of calcinurin.
• Immunosuppressants like cyclosporin A and tacrolimus bind and activate immunophilins resulting in immunosuppressive effects.

B cell responses and antibodies

• B cells produce immunoglobulins.
• Immunoglobulin that binds to antigen is called antibody.
• 9  isotypes in humans: IgM, IgD, IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgE.
• Maximum production: IgA.
• BCR binds antigen with high affinity in contrast to TCR.
• T- independent- B cell antibody response: B cells respond to certain antigens in the absence of antigens.
• B cell responses don't mature, they don't enter the memory pathway.
• Mutation in gene for Gp39 lead to X- linked hyperimmunoglobulinemia M syndrome: deficiency of immunoglobulin isotypes.
•  IgM : primary response Immunoglobulin
•  IgE, IgG, IgA: Secondary response immunoglobulins( by memory B cells).

Hello readers. I am writing the basic concepts of immunity and inflammation. I hope it is helpful to the students and any other reader. I have tried to make it as simple as possible.

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     Reference: Carranza's Clinical periodontology.