3 Types of Immunity: Innate and Acquired

Dr. M. N. Gupta

Objectives

 

  •  To understand the basic difference between innate and acquired immunity
  •  To learn about various cells involved in innate immunity
  •  To learn about various soluble factors involved in innate immunity
  •  To understand how innate immunity also has a limited specificity towards pathogen via pattern recognition

 

2. Concept Map

 

Innate Immunity

 

There are two types of Immunity

 

(a) Innate

 

(b) Acquired

 

Innate immunity and Acquired immunity complement each other. The response of the innate immunity system is fast. It has some specificity for microbes. It has no memory. Every time the innate immunity system encounters an antigen, it reacts ab initio. Hence, the innate immune response is not improved by repetitive invasion by the same antigen. The above three features distinguishes it from acquired immunity

 

Acquired immunity is also called Adaptive immunity and it consists of antibody mediated and T-cell mediated responses. This will be discussed in later modules.

 

 

This module will focus on Innate Immunity.

 

Both soluble factors and some cells participate in the Innate immune response

 

Innate immune system is present right from the birth. So, before acquired immune system develops, it protects the infant. In fact, this system changes very little during the lifetime. Inflammatory response to an infection is also part of the innate immune response.

 

The cells responsible for the innate immune response are:

(a) Phagocytes

(b) Natural Killer Cells (NKC)

(c) Mast Cells

(d) Dendritic Cells

(b) The NKC (lower left) is locating, binding and attacking a large cancer cell

 

Molecules responsible for the Innate immune response Several classes of molecules also participate in the innate immune response

 

(a) Antimicrobial Peptides

 

Epithelial cells of the respiratory, gastrointestinal and genitourinary tracts produce these antimicrobial peptides.

 

If the microbial infection breaches the barrier of the epithelial cells, it encounters phagocytic cells. One of the modus operandi of phagocytic cells during innate immune response is to produce some antimicrobial peptides

 

These peptides are made up of less than 60 amino acids.

 

They may have a α-helical structure, a β-sheeted structure, a αβ-mixed structure or just a non-αβ extended structure

 

Properties of Antimicrobial Peptides (AMPs)

 

AMPs cover a wide spectrum of antimicrobial properties. This range includes both gram positive and gram negative bacteria, virus, fungi. Many have net positive charge.

 

Mechanism of action includes altering the membrane permeability of the cells of the pathogen.

 

Some AMPs exploit chemotaxis and attract T-cells (part of the acquired immune system) and dendritic cells. Thus AMPs are part of the co-operation between innate and acquired immune system.

 

 

It is believed that we may not have yet discovered all AMPs.

 

AMPs are either produced constitutively or produced via pathogen associated molecular patterns.

 

The latter operates via pattern recognition receptors which are present on the following cells of the innate immune system. Note the relationship between cells and soluble factors of the innate immune system

  • Macrophages
  • PMNs
  • Myeloid and plasmacytoid dendritic cells
  • Some epithelial cells

This mechanism is responsible for the limited specificity of the innate immune system.

 

It results in removal of microbes with common or similar surface structural motifs through a single functional response.

 

Apart from this, some soluble pattern recognition receptors also exist All those receptors can also bind to the self-components and participate in apoptosis (clearing dead cells).

 

Various Pattern Recognition Receptors (PRRs)

 

Toll-Like Receptors (TLRs)

 

These are among the ancient receptors from the evolutionary perspective

 

Initially Toll receptor was discovered in the fruitfly Drosophila and later various Toll-like receptors were found in the mammalian systems

 

While most of the TLRs are present on the cell surface (especially on mono nuclear phagocytes), some are also present on endosomes.

 

The family of TLRs recognize wide range of pathogens

 

TLRs are integral proteins having intracellular domains

 

Upon binding to the ligands on the pathogen, the cells containing TLRs produce cytokines.

 

Thus the consequences are:

 

  • Inflammatory response due to cytokines which include TNF-α and IL-2
  • Enhances the capacity of the cells to kill microbes
  • Augments its antigen presentation capacity

TLR2 can form heterodimers with TLR1 or TLR6 with tri-acyl proteins and di-acyl proteins as ligands TLR3, TLR7, TLR8, TLR9 are intracellular TLRs found on endosomes.

 

Some additional information on TLRs

 

TLR10 (also known as CD290) has been reported; its ligands are unknown but its cellular distribution is plasmacytoid dendritic cells.

 

TLRs have extracellular domain rich in leucine rich repeats and a cytoplasmic domain that is involved in the signal transduction process.

 

These germline coded molecules detect invading pathogens and trigger expression of cytokines and co-stimulating molecules.

 

The best characterized member is TLR4. Apart from LPs, it also binds to host proteins during damage, infection and inflammation like HSP-60 and a fibronectin variant.

 

The recognition of LPs by TLR4 also requires CD14 as a coreceptor and LPs binding protein from serum which brings LPs to CD14.

 

Mannose Receptor (MRs) (CD206)

 

It is a Ca2+ dependent 180 kD integral protein, has 8 carbohydrate lectin domains which recognizes mannosyl/fucosyl recognition patterns on pathogens entering through mucosal surfaces.

 

It also has a terminal lectin domain which recognizes sulfated carbohydrate groups.

 

Macrophages (throughout the body), endothelial cells and dendritic cells have these receptors.

 

MRs link the innate immune response with acquired immunity as the pathogens are internalized and degraded in endosomes and displayed on antigen presenting cells (will be clearer once acquired immunity has been discussed)

 

The receptor also binds host proteins such as myeloperoxidase, lysosomal hydrolases and some hormones.

Soluble Pattern Recognition Receptors

 

Many soluble proteins recognize PAMPs (Pathogen associated molecular patterns)

 

Many of these carbohydrate recognizing protein are part of the innate immunity

 

Complement System

 

It consists of 20 soluble glycoproteins which are constitutively present in blood and other body fluids Many of these are produced by hepatocytes and monocytes.

 

On being triggered, a cascade of reactions occur which enables protection against pathogens through inflammation, enhanced phagocytosis or lysis of pathogenic cells.

 

The triggering can occur through three different pathways

Acute Phase Proteins

 

These include C-reactive Proteins (CRPs), Complement components, MBL, metal binding proteins and protease inhibitors

 

These are mostly produced by liver either de novo (e.g. CRP) or their low level increases (e.g. fibrinogen) rapidly

 

These are particularly important in defense against bacteria and protozoa

 

Activated macrophages and NK cells release cytokines (IL-6 being very important) and this leads to hepatocytes responding by producing acute phase proteins.

 

Overall, acute phase proteins limit tissue damage by

  • Microbial infections
  • Trauma
  • Malignancy
  • Diseases like rheumatoid arthritis
  •  These proteins are important in tissue repair as well

 

Many acute phase proteins occur as similar pentagonal subunit association and hence are classified as Pentraxins. Examples are: CRP, SAA, SAP..

 

All Pentraxins are Ca2+ dependant carbohydrate binding proteins.

 

Cytokines

It is better to take the above not as a classification but a definition of terms as there is some overlap among those.

  •  Interleukins: 35 interleukins have been described, IL1-IL12 are better characterized
  •  Some are also produced by lymphocytes and are thus lymphokines as well
  •  These can be placed in four families based upon structural similarities

Like other cytokines, these have diverse functions and highlight the overlap between innate and acquired immunity.

 

Other Important Cytokines

 

Chemokines

 

More than 50 identified so far, these are 8-10 kDa peptides responsible for chemotaxis of lymphocytes, monocytes and neutrophils.

 

There are conserved cysteine residues, their position and amino acid sequences form the basis of 4 classes of chemokines.

  •  Receptors for chemokines are integral membrane proteins and G-protein mediated signal transduction operates
  •  Hence these molecules activate and direct effector cells to the infection or tissue damage sites. These also control leukocyte migration in tissues.

Interferons

 

 

 

These proteins protect against viral infections

 

The three types are:

Many texts prefer treating IFN-α and IFN-β as a single class. These actually have the same receptor.

 

Interferons from the activated cells or virally infected cells bind to receptors on nearby cells which in turn produce antiviral proteins.

 

Antiviral proteins limit viral replication by either blocking protein synthesis initiation or cause mRNA degradation of viral proteins.

 

Inteferons are part of the pro-inflammatory molecules. IL-1, TNFα, endotoxin (from cell walls of the gram negative bacteria) induce IFN-α and IFN-β release.

 

IFN-γ belongs more to the acquired immune system and plays a critical role in induction of Tn response.

 

Some other important cytokines

  • Migration Inhibition Factor (MIF)

 

Released by activated T-cells, it inhibits the migration of macrophages and thus enhances their action at the site of inflammation.

 

Tumour necrosis factor (TNF) and lymphotoxin (LT)

 

Both are structurally related and in fact LT is also called TNFβ. TNFα is produced by macrophages and some other cells whereas TNFβ is not a part of the innate immunity as it is produced by Tc cells. Their actions include:

  •  Enhancing adhesion of leukocytes to vascular endothelium
  •  Mobilization of fat resulting in cachexia (washing)
  •  Apoptosis by activating caspases

Transforming growth factor-β (TGF-β)

 

These are group of 5 cytokines released by many cells including macrophages and platelets. Actions include increasing production of the extracellular matrix protein and controlling proliferation of B- and T-cells.

 

CSFs including granulocyte-monocyte CSF (GM-CSF), granulocyte CSF (G-CSF) and monocyte CSF (M-CSF)

 

These are involved in the development, differentiation and expansion of cells of myeloid series.

 

Cells of the innate immune system

 

  1. Phagocytes
  • (i) Neutrophils: Also called polymorphonuclear cells (PMNs), they are a major part of the blood leukocyte population. These have granules containing peroxidases, alkaline and acid phosphatases and defensins. These are responsible for their ability to destroy cells.
  • (ii) Macrophages: These are mononuclear phagocytes which are distributed throughout the body as tissue bound cells. Endocytopsis of the microbe followed by fusion of the phagosomes with lysosomes. Microbe destruction involves both oxygen dependant (O2 radicals, NO) as well as oxygen independent (eg: myeloperoxidase) mechanisms are involved.
  1. Natural Killer Cells (NK Cells)

These are present in tissues as well and majority is in circulation. These offer protection against viruses and some tumours. Actions include inducing apoptosis by releasing perforins and releasing INF-γ to protect viral infection of neighbouring cells.

  1. Mast Cells and Basophils
  •  Mast cells and Basophils are present in connective tissues and circulation respectively
  •  These have similar morphology and functions
  •  Upon degranulation, these release pharmacological mediators such as histamines and cytokinins. The result is vasodilation, increase in vascular permeability and leukocytic migration
  1. Dendritic Cells (DCs)

These are links between innate and acquired immunity and interact with T-cells or B-cells and thus induce/ regulate immune responses.

 

  1. Other cells which have roles in innate immunity

 

a.) Erythrocytes: Bind and remove small immune complexes

 

b.) Eosinophiles: Granular leukocytes which release toxic proteins which kill parasites

 

c.) Platelets: release mediators that activate complement cells

 

d.) Epithelial cells: The role of these in releasing AMPs has already been mentioned

 

 

Much of what has been introduced here will be discussed in more detail in later modules.

 

To Summarize:

  •  Innate Immunity and Acquired Immunity are two kinds of immune responses.
  •  Innate immunity is mostly non specific and does not depend upon previous encounter
  •  Innate immune response is mediated by soluble factors as well as cells
  •  Pattern recognition receptors recognize pathogen associated molecular patterns