humoral immunity

The humoral immune response employs antibodies secreted by B lymphocytes, and is a component of the adaptive immune response. In addition to antibody production, the immune system secretes chemical mediators.

Elements of the humoral response include:
● secretion of antibodies
___● neutralization of pathogens and toxins
___● activation of classical complement pathway
___● opsonin production
● stimulation of cellular responses
___● formation of germinal centers
___● activation of helper T cells (Th2)
___● production of memory B lymphocytes
___● opsonin-directed phagocytosis and elimination of pathogens
● chemi-genetic responses
___● isotype switching between immunoglobulin types
___● affinity maturation (combining somatic hypermutation and affinity based clonal selection)
___● production of immune cytokines
___● C9 complement membrane attack complex
___● production of acute phase-inflammatory response mediators

Tables  Complement Receptors  Cytokines  Fc receptors  Immune Cytokines  Immunoglobulins  Interferons  Scavenger Receptors  Toll-like Receptors

tags [Immunology] [antibodies] [cytokine] [helper T]

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immune cytokines

Cytokines are small proteins that regulate and mediate immunity, inflammation, and hematopoiesis. They are secreted de novo in response to immune stimuli, and usually act briefly, locally, at very low concentrations (the exception being endocrine action at distant cells). All cytokines possess four conserved cysteine residues, and are divided into two families based upon the contiguity (CC) or separation of cysteine residues (CXC).

The orchestration and regulation of cytokine production during inflammatory responses constitutes a key determinant of both the resolution of challenge and the limitation of host tissue damage. Cytokines bind to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter cellular activity (gene expression). Cytokines are often produced in cascades.

Tables  Immune Cytokines  Fc receptors  Immunoglobulins  Interferons

▼ actions : chemokine : chemokine family receptors : classification of cytokines : colony-stimulating factors (CSF) : cytokine cascade : cytokine effects : cytokine receptors : cytokine secreting cells : distance of cytokine action : granulocyte colony-stimulating factor (G-CSF) : granulocyte-macrophage colony-stimulating factor (GM-CSF) : hematopoietin family receptors : interleukins, interleukins as largest group : interferon family receptors (IFNR) : largest group of cytokines : lymphokine : lymphotoxins : macrophage colony-stimulating factor (M-CSF) : mechanism of cytokine action : monokine : receptors : search for novel cytokines : target cells : tumor necrosis family receptors
(TNFR) ▼

Actions of cytokines include:
a) up- or down-regulation of the expression of membrane proteins (including cytokine receptors),
b) secretion of effector molecules: histamine release; antibody secretion - IgA, IgG1, and IgE synthesis; IL-1 synthesis; cytokine production; MHC Class II; and CAM expression
c) cellular proliferation
d) chemotaxis of neutrophils, monocytes, and T cells
e) cellular differentiation
f) inflammation
g) phagocytosis
h) death of tumor cells
i) elimination of pathogens

Cytokines are classified according to the cells that produce them:
a) Lymphokines - produced by lymphocytes
b) Monokines - produced by monocytes,
c) Chemokines - chemotactic activities
d) Interleukins - manufactured by one leukocyte to act on other leukocytes.

The cells that produce cytokines include B cells, T cells, dendritic cells, NK, Tc, Th, Th1, Th2, endothelial cells, mast cells, plasma cells, progenitor, marrow stroma, thymus stroma, and tumor cells, along with fibroblasts, leukocytes, monocytes, and macrophages.

Cytokine function may be targetted at:
a) The cells that secrete them (autocrine action),
b) Local cells (paracrine action),
c) Distant cells (endocrine action).

Target cells include: B cells, T cells, NK, Tc, Th, Th2, stem, mast cells, plasma cells, progenitor, tumor cells, phagocytes, neutrophils, monocytes, and macrophages.

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine secreted by several cell types, including mononuclear cells of the immune system and pituitary cells in the brain. Functional promoter polymorphisms in the MIF gene affect the clinical presentation of systemic sclerosis (SSc, scleroderma) and confer susceptibility to systemic lupus erythematosis (SLE). MIF counteracts cortisol-induced inhibition of inflammatory cytokine secretion, and employs the CD74 receptor.

Cytokines bind to specific membrane receptors:
a) Hematopoietin family receptors - dimers or trimers with conserved cysteines in their extracellular domains and a conserved Trp-Ser-X-Trp-Ser sequence.
The two subunits are i) cytokine-specific, and ii) signal transducing.
Cytokine binding promotes dimerization of the alpha and beta subunits, which then associate with cytoplasmic tyrosine kinases to phosphorylate proteins and activate mRNA transcription. Examples - receptors for IL-2 through IL-7 and GM-CSF.

Colony-stimulating factors (CSFs) are glycoprotein molecules that support growth of hematopoietic colonies. Interleukin 3 (IL-3) exhibits broad activity in the proliferation and differentiation of erythroid, megakaryocytic, and myeloid lineage progenitor cells.

Macrophage colony-stimulating factor (M-CSF, CSF1) acts selectively on the macrophage lineage, while granulocyte colony-stimulating factor (G-CSF) acts selectively on cells of the granulocyte lineage.

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have pleiotropic activating effects on mature leukocytes, which can improve leukocyte function, facilitating eradication of microbial infections. G-CSF activates neutrophils, while GM-CSF activates neutrophils, eosinophils, and monocyte/macrophages.

G-CSF is a 19.6 kDA glycoprotein that exists in two forms, comprising either 174 or 180 amino-acids. It is produced in a number of different tissues and stimulates granulopoietic proliferation and differentiation in the bone marrow. GM-CSF is a 14.6 kDa globular protein of 128 amino acids that contains two intramolecular disulfide bonds and two potential N-linked glycosylation sites. It is produced by endothelial cells, monocytes, fibroblasts and T-lymphocytes. GM-CSF is a hematopoietic growth factor that stimulates the development of macrophages and neutrophils, and inhibits neutrophil migration while enhancing the functional activity of the mature end-cells. It also promotes the proliferation and development of early erythroid megakaryocytic and eosinophilic progenitor cells.

b) Interferon (IFN) family receptors have the conserved cysteine residues but not the Trp-Ser-X-Trp-Ser sequence, and include the receptors for IFNα, IFNb, and IFNγ.

c) Tumor Necrosis Factor family receptors possess four extracellular domains, and include receptors for soluble TNFα and TNFβ as well as membrane-bound CD40 (important for B cell activation and macrophage activation) and Fas (which signals the cell to undergo apoptosis). TNFα is lymphotoxin β (LT), where the lymphotoxins occur either as homotrimers of LT-α (LT-α3) or as heterotrimers of one LT-α subunit plus two LT-β subunits (LT-α,β2).[s]

d) Chemokine family receptors have seven transmembrane helices and interact with G protein. This family includes receptors for IL-8, MIP-1 and RANTES. Chemokine receptors CCR5 and CXCR4 are used by HIV to preferentially enter either macrophages or T cells.

Cytokines are often produced in cascades, as one cytokine stimulates its target cells to produce additional cytokines. Cytokines are redundant in their activity, in that different cytokines can stimulated similar functions. Different cell types may secrete the same cytokine, or for a single cytokine may act on several different cell types (pleiotropy). Cytokines can also act synergistically with two or more cytokines acting together, or antagonistically with cytokines causing opposing activities.

Interleukins comprise the largest group of cytokines, stimulating proliferation and differentiation of immune cells. The group includes Interleukin 1 (IL-1), which activates T cells; IL-2, which stimulates proliferation of antigen-activated T and B cells; IL-4, IL-5, and IL-6, which stimulate proliferation and differentiation of B cells; Interferon gamma (IFNγ), which activates macrophages; and IL-3, IL-7 and Granulocyte Monocyte Colony-Stimulating Factor (GM-CSF), which stimulate hematopoiesis.

Short half lives, low plasma concentrations, pleiotropy, and redundancy combine to make the isolation and characterization of cytokines difficult. Search for novel cytokines is often conducted at the DNA level, identifying genes that are similar to known cytokine genes.

▲ actions : chemokine : chemokine family receptors : classification of cytokines : colony-stimulating factors (CSF) : cytokine cascade : cytokine effects : cytokine receptors : cytokine secreting cells : distance of cytokine action : granulocyte colony-stimulating factor (G-CSF) : granulocyte-macrophage colony-stimulating factor (GM-CSF) : hematopoietin family receptors : interleukins, interleukins as largest group : interferon family receptors (IFNR) : largest group of cytokines : lymphokine : lymphotoxins : macrophage colony-stimulating factor (M-CSF) : mechanism of cytokine action : monokine : receptors : search for novel cytokines : target cells : tumor necrosis family receptors (TNFR) ▲

Tables  Immune Cytokines  Cell signaling  Receptor Tyrosine Kinases(RTK)  Second Messengers  Phosphate-handling Enzymes  Cell Adhesion Molecules (CAM) .

· adenylyl (adenylate) cyclase ф antibodies ф antigen ф B cells · cadherins · calcium ions · cAMP-dependent protein kinase · CDKs ф cellular response · chemotaxis ф class-switch recombination ф clonal selection ф complement system ф costimulation · cyclin-dependent kinases · cytokine receptors · DAG ф dendritic cells · diacylglycerol · DNA ligases · ERKs · GPCRs · GPCR families ф granulocytes · guanylate cyclases · guanyl cyclase ф helper T cell ф hematopoiesis ф humoral immunity · Ig superfamily ф immune response ф inflammatory response · inositol triphosphate · integrins · IP3 ф leukocytes ф leukocyte adhesion cascade ф lymphokines ф macrophages · MAP kinases ф macrophages ф MHC ф migration · mitogen activated protein kinases ф monocytes ф neutrophils ф pathogens ф pattern-recognition receptors ф phagocyte · phosphatases · phosphodiesterases ф plasma cells · phospolipases · phosphorylation · PKA · PKC · phospholipase C-gamma · protein kinase A · protein kinase C · protein tyrosine kinases (PTKs) ф receptors · receptor tyrosine kinases · second messengers · second messenger cAMP · second messenger cGMP · selectins ф signaling · signal transduction ф surface receptors ф T cells · TNFs · two-component systems ·

Tables  Fc receptors  Immune Cytokines  Immunoglobulins  Interferons  Cell Adhesion Molecules  Cell signaling  Receptor Tyrosine Kinases (RTKs)  Receptor Signal Transduction  Second Messengers 

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immune response

The immune response is mounted by cells of the immune system in response to invasion by pathogens. Immune responses are classifed as passive or active, innate or adaptive, and cellular or humoral.

▼ activation B : activation T : active/passive : adaptive immune response : anergy : autoimmune : blood : cells : cellular immune response : cellular participants : classification : costimulation : danger hypothesis : humoral immune response : humoral participants : innate immune response : pattern recognition receptors : phagocytes : molecular participants : self-other : surface receptors ▼

The immune system is intimately connected with the hematologic system since white blood cells (leukocytes, including B- and T-lymphocytes) are key players in the lymphoid system. Cellular participants in the immune and inflammatory responses include :
● phagocytic cells (dendritic cells, monocytes and macrophages, and granulocytes)
● antigen presenting cells (dendritic cells, macrophages, B lymphocytes, helper T cells)
● antibody producing cells (plasma cells)
● cytotoxic cells (CTL, NK)
● regulatory cells (APCs, helper T cells, regulatory T cells)
● cells-in-waiting (memory B cells, monocytes)
● chemical releasing cells (basophils, eosinophils, neutrophils; mast cells - histamine, cytokines; hepatocytes - complement proteins)

Anergy toward self-targets operates as one self-tolerance mechanism to control the autoreactive cells found in disease-causing autoimmunity. Immune responses ideally distinguish between self and other. In 1994, Polly Matzinger proposed an alternative to the widely established concept that the immune system primarily discriminates self from non-self. This alternative hypothesis suggested that the immune system is mainly adapted to recognize and respond to signals generated in a 'dangerous' situation that involves cell damage (Matzinger, 1994). This model, which became known as the 'danger' hypothesis, is based on the idea that the crucial signals for the initiation of immune responses are endogenous, not exogenous (Matzinger, 2001). According to this hypothesis, the power lies with the tissues: the activation state of APCs would depend on the health of cells in their neighbourhood. Accumulating evidence suggests that both exogenous and endogenous adjuvants contribute to the initiation of immune responses by activating APCs (Rock et al, 2005).[s=fft]

Immune responses are classifed as passive or active, innate or adaptive, and cellular or humoral.

Passive measures to prevent pathogenic incursions are provided by physical barriers to invasion – the skin, secretions, and ciliary action. Should pathogens pass beyond the physical barricade, then active innate and adaptive immune reactions mount a defense.

Innate immune responses employ phagocytic cells that are circulating or tissue emplaced – granulocytes, monocytes, dendritic cells, macrophages, and B lymphocytes. The early, innate response also employs chemical responses – chemical-mediated inflammation; the complement cascade; antimicrobial peptides; and, pattern-recognition receptors (PRR), including toll-like receptors. The innate system is considered to constitute an evolutionarily older defense strategy, and it is the predominant immune system exhibited by plants, fungi, insects, and primitive metazoa.

An induced, adaptive response begins when foreign or pathogenic substances (antigens) are 'recognized' by cells of the lymphoid system, stimulating a co-ordinated cellular/humoral response depending upon the nature of the pathogen.

Surfaces of cells of the immune system are coated with proteins and receptors that participate in cellular signal transduction, enabling regulatory interaction:
● clusters of differentiation – a defined subset of cellular surface receptors (epitopes) on B and T lymphocytes that identify cell type and stage of differentiation, and which are recognized by antibodies.
● B cell receptors (BCR) comprising one of thousands of distinct immunoglobulin superfamily molecules generated through VDJ recombination.
● T cell receptors (TCR) with heterodimers of α and β chains or γ and δ chains with Ig-like domains. Each TCR originates in a single allele and binding with a single specificity (CDR3 for antigens and CDR1-2 for MHCs).
● major histocompatibility complex (MHC) molecules of classes I, II, and III, participate in lymphocyte recognition and antigen presentation.

B lymphocytes perform the humoral immune response , and are activated when naïve B cells encounter their specific, cognate antigen. Secreted cytokines promote the proliferation of single clones of B cells that express that immunoglobulin surface receptor (BCR) that already possesses VDJ recombination-generated affinity for the antigen.

Costimulation involves ligand-receptor interactions at the surfaces of a responder lymphocyte and an "accessory" cell – APCs for activation of T cells, and helper T cells for activation of B cells. Assisted by costimulation from helper T cells, B cells may undergo differentiation into plasma cells, which secrete copious quantities of the monoclonal antibody, or into memory B cells, which are primed for rapid response to a repeated exposure of the priming antigen.[]diagram B[]

T lymphocytes participate in the cellular immune response, and are (first signal) activated by engagement of their surface receptor (TCR), which ensures antigen specificity and MHC restriction of the response. Delivery of first signal (TCR engagement) in the absence of costimulation by second signaling results in apoptosis or anergy. Synergistic signaling by (second signal) costimulatory molecules is also necessary to sustain and integrate TCR signaling to stimulate optimal T cell proliferation and differentiation. []diagram T[]

In addition to antibodies produced by plasma cells, a number of molecule types participate in the humoral response, including:
● complement cascade – anaphylatoxins and opsonins
● fibronectin
● coagulation factors
● interferon
● lysozyme, phospholipase
● interleukin-1 (IL-1), inflammatory kinins
● iron-binding lactoferrin and transferrin
● TNF-α

▲ф activation B : activation T (activation B : activation T : activation complement cascade ) : active/passive : adaptive immune response : anergy ф anergy ф antibodies ф antigen ф APCs ф autoimmunity : autoimmune ф B cells ф basophils : blood ф blood ф CD : cells : cellular immune response : cellular participants ф cellular response : classification ф CD ф cellular response ф clonal selection ф complement system ф costimulation : costimulation ф cytolysis ф cytotoxicity : danger hypothesis ф dendritic cells ф eosinophils ф granulocytes ф helper T cell ф hematopoiesis ф humoral immunity ф HIV/AIDs : humoral immune response : humoral participants ф immune cytokines ф immune response ф immune tolerance ф inflammatory response : innate immune response ф killer T cells ф leukocytes ф leukocyte adhesion cascade ф lymphocytes ф lymphokines ф lymphoid system ф macrophages ф MHC ф migration : pattern recognition receptors : phagocytes ф phagocyte ф plasma cells ф receptors ф signaling ф surface receptors : molecular participants : self-other : surface receptors ф surface receptorsT ф T cells ф thymus V ф vaccines ф VDJ recombination▲ф

Tables  Complement Receptors  Cytokines  Fc receptors  Immune Cytokines  Immunoglobulins  Interferons  Scavenger Receptors  Toll-like Receptors

Toll, A New Piece in the Puzzle of Innate Immunity. Wright SD. [Free Full Text Article] J Exp Med. 1999 Feb 15;189(4):605-9.

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interferons

Interferons are immune cytokines that are classified as type I, II, or III according to the receptors through which they signal. Interferon (INF) family receptors have conserved cysteine residues and include the receptors for IFN-α, IFN-β, and IFN-γ.

● IFN type I – bind to the IFN-α receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains – subtypes of IFN-α, IFN-β (image at left) , IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, IFN-ζ (limitin)

● IFN type II – IFN-γ receptor (IFNGR) complex comprising two subunits each of molecules designated IFNGR1 and IFNGR2 – singel type IFN-γ (image at right)

● IFN type III –receptor complex comprising IL10R2 (CRF2-4) plus IFNLR1 (CRF2-12) – types IFN-λ1(IL29), IFN-λ2 (IL28A), IFN-λ3 (IL28B) (image)

Table  Interferons

Cellular secretion of interferon is stimulated by:
● constituents such as CpG DNA from microbial pathogens – bacteria (endotoxin, flagellin, CpG) and viruses (viral glycoproteins, viral RNA, CpG)
● mitogens
● other cytokines, such as the interleukins (1, 2, 12), TNFs, and colony-stimulating factors

Interferon actions:
● anti-tumor
● antiviral
● activation of macrophages and NK cells
● presentation of microbial peptides to T cells through enhancement of MHC classes I and II

 Fc receptors  Immune Cytokines  Immunoglobulins  Interferons

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isotype switching

Isotype switching is a characteristic feature of the humoral immune response, in which a switch from IgM to other Ig isotypes follows first exposure to an antigen. Affinity maturation ensures that repeated exposures to the same antigen will provoke greater antibody ligating affinity of the antibody secreted by successive generations of plasma cells.

Isotype switching is regulated by T cell-produced immune cytokines, such as interleukin-4 (IL-4), interferon-γ (IFN-γ), and TGF-β, which direct B cells to switch to specific Ig classes.

Tables  Fc receptors  Immune Cytokines  Immunoglobulins

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pathogens

Pathogens are agents that disrupt the physiological operations of an organism, and are acquired through infection.

Pathogens include:
● bacteria
● fungi
● parasites
● prions (proteins)
● protozoa
● viruses

Some colonization by other organisms is harmless or helpful. Human skin, mouths, and intestines play host to numerous commensal bacteria and fungi that cause little problem, yet our innate immune systems quickly respond to pathogen-associated molecular patterns (PAMP).

Higher photosynthetic unicellular and multicellular organisms (algae and plants) ultimately acquired chloroplasts through serial endosymbiotic transfers from Cyanobacteria to an ancestral eukaryote about 1.4 billion years ago [im]. Algae, animals, fungi, plants and protists almost certainly acquired mitochondria through serial endosymbiotic transfers [im] events between an ancestral eukaryote and Rickettsiales.

Tables  Fc receptors  Immune Cytokines  Immunoglobulins

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