Historically, the term immunology comes from the word ‘immunitas’. Immunity means protection. All the mechanisms participate in the protection procedure, known as the immune system. The collective & coordinated response of the immune system towards a foreign substance is called the immune response.
An English physician Edward Jenner first introduced the term vaccine including creating a vaccine against cowpox.
TYPES OF IMMUNITY -
There are two types of immunity, innate immunity & adaptive immunity.
The innate immune system is the oldest immune system. The innate immune system is even present in sponges. Innate immunity activates immediately after entering a pathogen. Adaptive immunity is activated by innate immunity & it takes a few days for adaptive immunity to activate correctly. Adaptive immunity is more vigorous than innate immunity.
In invertebrates, innate immunity is present but adaptive immunity is absent, whereas both types of immunity are present in vertebrates.
Lymph nodes that activate the immune system to fight against infection are only present in Aves & Mammals.
Macrophages connect the innate branch of our immunity to the adaptive branch
INNATE IMMUNITY
CHARACTERISTICS -
(1) The innate immune system responds similarly to all pathogens.
(2) In most cases, the innate immune system activates the adaptive immune system.
(3) The innate immune system can recognize the structures that are the characteristics of pathogens.
COMPONENTS OF INNATE IMMUNE SYSTEM -
The components of the innate immune system consist of -
(1) Epithelial barriers
(2) Cells &
(3) Proteins
1) Epithelial barrier - A physical barrier is produced by the epithelial surface between the host tissue & microbes. Defensins, a cysteine-rich peptide is released by the epithelia which has antibacterial functions. Defensins are made up of 29-34 amino acids. During inflammation, the secretion of defensins increases.
During inflammation, neutrophil recruitment occurs near the epithelial surface. Neutrophils secret TNF & IL1. Epithelial cells possess receptors for TNF & IL1. The binding of TNF & IL1 with their respective receptors causes the increase of the defensin secretion.
2) Cells - Apart from NK cells, intraepithelial T cells & B1 cells take place in innate immunity.
B1 cells produce the IgM antibody. IgM acts on the lipopolysaccharide layer of bacteria & destroys it. Intraepithelial cells recognize any cells that possess CD1 protein. CD1 protein actually resembles MHC class 1. Intraepithelial cells can activate macrophages.
The bacterial cell wall is composed of glycoprotein & glycolipid. In the case of bacteria, the glycoprotein possesses a terminal carbohydrate, mannose & the glycolipid ends with fucose. But in the case of humans, glycolipids & glycoproteins end with sialic acid & N acetyl glucosamine respectively. Neutrophils can recognize mannose & fucose.
Macrophages recognize the glycosylated proteins of bacteria. Macrophages differentiate between bacteria & human glycosylated proteins via the presence of mannose. Macrophages possess receptors for mannose, known as CD206.
TLR RESPONSE
Toll-like receptors (TLR) are transmembrane protein that helps in the recognition of a variety of microbe-derived molecules & triggers the innate immune response. Toll-like receptor possesses sequence homology with toll proteins in the fruit fly (Drosophila). In Drosophila melanogaster, only innate immunity is present. Toll protein in the fruit fly performs a significant role in the innate immune system. Toll proteins perform two functions -
(1) Toll proteins have antimicrobial actions.
(2) Toll proteins help in the formation of dorso- ventral axis of drosophila melanogaster during embryogenesis.
10 mammalian TLRs have been identified.
TLR structure -
The toll-like receptor contains an extracellular & an intracellular domain. The extracellular domain contains leucine-rich repeats & cysteine-rich repeats and the intracellular domain contains the Toll/ IL1 receptor domain (TIR domain).
TIR domain has sequence homology with intrleukin1.
All TLRs dimerize to perform downstream signaling. TLR 2 along with TLR1 or TLR 6 form heterodimers. TLR 3,4,5,6,7,8 & 9 forms homodimer.
Functions of different types of TLR -
TLR molecules are of two types based on their positions.
(1) TLRs present on the cell membrane
(2) TLRs present on the endosome.
1) TLRs PRESENT ON CELL MEMBRANE -
All heterodimers are present on the cell membrane.
TLR2 & TLR6 complex and TLR2 & TLR6 complex can recognize lipoproteins, peptidoglycan (a component of the bacterial cell wall), zymogen (a component of the cell wall of yeast) & lipoarabinomannan.
TLR5 recognizes flagellin & TLR4 along with MD2 when comes in contact with lipopolysaccharide, TLR4 helps in the activation of macrophages.
2)TLRs PRESENT ON ENDOSOME -
The bacteria are phagocytosed by the endosome & inside the endosome, the RNA & DNA of bacteria are found because of their raptured cell wall. TLRs which are present on endosomes can recognize the bacteria;l DNA & RNA.
TLR3 recognizes dsDNA. TLR7 can recognize ssRNA & TLR9 recognizes unmethylated CPG. After recognition, TLRs start downstream signaling.
TLR4 SIGNALING
TLR4 is present on the cell membrane and it can recognize lipopolysaccharide, an important component of the bacterial cell wall. When LPS binding protein binds with MD2, the dimerization of TLR4 takes place. Here, MD2 acts as an adaptor protein.
There are two signaling pathways, accomplished via TLR4 signaling.
(i) MYD88 dependent pathway
(ii) MYD88 independent pathway
(i) MYD88 dependent pathway -
(1) After the dimerization of TLR4, the TIR domain is activated. An adaptor protein TIRAP (TIR domain-containing adaptor protein) associated with the TIR domain helps in the activation of MYD88.
(2) Actually, inside the cytoplasm MYD88 along with IRAK4 (interleukin 1 receptor-associated kinase) & IRAK1 forms a complex, known as mydosome. After activation MYD88 activates IRAK4 which in turn activates IRAK1.
Actually, IRAK4 possesses two domains, one domain binds with MYD88 protein & another domain possesses kinase activity. Upon activation via MYD88 protein, the kinase domain helps in the activation of IRAK1.
(3) As the IRAK1 gets activated, it comes out from the complex, myddosome & helps in the activation of a ubiquitin ligase, TRAF6 (TNF receptor-associated factor 6).
(4) A protein, TAK1 which is inhibited by TAB1, TAB2 &TAB3 activated upon the removal of these inhibitory proteins via the TRAF6. TRAF6 helps in the ubiquitination of these inhibitory proteins. As they are ubiquitinylated, they undergo proteasomal degradation.
(5) The activated TAK1 activates the inhibitor of kappa beta kinase (IKK).
NF𝜿𝛃, a transcriptional factor that possesses nuclear localization sequence (NLS) is inhibited by inhibitor kappa B. IKK phosphorylates inhibitor kappa B to activate the transcriptional factor.
(6) After the removal of the inhibitor, NF𝜿𝞫 translocates into the nucleus & helps in the activation of the pro-inflammatory gene. The pro-inflammatory gene upon activation transcribes cytokinins & TNF.
(ii) MYD88 independent pathway -
(1) An adaptor protein, TRAM activates TRIM which in turn helps in the activation of a ubiquitin ligase, TRAF6.
(2) TRAF6 activates TAK1 via the removal of inhibitory proteins. TAK1 activates an inhibitor of kappa beta kinase which activates the transcriptional factor NF𝜿𝞫 via the removal of the inhibition from the NLS molecule of NF𝜿𝞫.
(3) Then NF𝜿𝞫 translocates into the nucleus and helps in the production of TNF & cytokinins via the activation of pro-inflammatory genes.
(4) TRIF also activates TRAF3 which in turn helps in the activation of IRF3. IRF3 also helps in the activation of genes.
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