cytotoxicity

Cytotoxic agents are toxic to cells:
● Cytotoxic physical agents
___ ● thermal (excessive heat or cold)
___ ● irradiation

● Cytotoxic drugs and chemicals have cytolytic, carcinogenic, mutagenic and/or teratogenic potential. Direct contact may cause tissue irritation, ulceration, and necrosis.
___ ● antineoplastic and immunosuppressive therapeutic agents
___ ● free radicals
___ ● strong acids and alkalis
___ ● secreted digestive enzymes and antimicrobials – lysozyme, phospholipase, defensins
___ ● secreted cytolytic molecules • FasL, granzymes, granulysin, perforin
___ ● phagocytosis-promoting opsonins – C3b of complement cascade, pulmonary surfactants

● Cytotoxic cellular immune responses
_ ● Antibody-dependent cell-mediated cytotoxicity (ADCC) is mediated by antibody-marking
_ ● Complement-dependent cytotoxicity (CDC) is mediated by the complement system (opsonin-induced phagocytosis performed by macrophages and neutrophils, anaphylatoxin induced histamine release by basophils and mast cells).
_ ● Lymphocyte-mediated cytotoxicity ('LMC') requires is independent of antibody-marking and the complement system

__ ● killer cells
___ ● non-specific 'attack' cells – eosinophils (IgE, CD67), macrophages (IgG, CD14), K cells (IgG), LAK cells (IL-2 activated cytolysis cells, lymphokine-activated killer cells), NK cells (CD16, CD56)
___ ● natural killers cells (NK) of innate immune system – have activating receptors and killer inhibitory receptors (KIR) – secrete cytolytic granzymes and perforin ('LMC')
___ ● natural killer T cells (NKT) – have αβ TCR plus some of the cell-surface molecules of NK cells – respond to glycolipid antigens presented by the cell-surface molecule CD1d (ADCC) – secrete IFN-γ (Th1 cytokine) plus IL-4 and IL-13 (Th2 cytokines)
___ ● cytotoxic T cells • (CD8 +) Tc matures into CTL (killer T cells) following activation (ADCC)
___ ● phagocytic cells engulf pathogens, often after pathogen coating by opsonins (CDC)

Tables  Fc receptors  Immune Cytokines  Immunoglobulins

tags [Immunology] [cytotoxicity] [cell death]

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evolution of immune and coagulation systems

Immune system
The innate immune system is ancient and displays roots roughly one billion years old, deep in the deuterostome branch of the bilaterians (pre-Cambrian). The lectin pathway (MBL - MASP) is homologous to the classical complement pathway, but utilizes opsonin, mannan-binding lectin (MBL, MBP) and ficolins rather than C1q. Diversified ficolins are of particular importance in invertebrates, which lack the adaptive immune response that evolved some 500 million years ago in jawed vertebrates.

Macrophage scavenger receptors appear to mediate important, conserved functions, so it was likely pattern-recognition receptors that arose early in the evolution of host-defense mechanisms. Eicosanoids play a prominent role in inflammatory/immune responses and the evolution of eicosanoid receptors has been analyzed on the basis of amino acid sequences. Eiconasoid receptors are located on a variety of cells, tissues, and organs and can be activated by either non-selective or selective ligands.

The more specific, versatile, memory-capable adaptive immune response evolved more recently, roughly 450 million years ago, and is found in the jawed vertebrates (gnathostomes) but not in invertebrates.

Although the B cells of higher vertebrates lack phagocytic capabilities, it has recently been demonstrated that B cells from teleost (bony) fish and amphibians display potent phagocytic activities. Particle uptake by B cells induced activation of 'downstream' degradative pathways, leading to 'phagolysosome' formation and intracellular killing of ingested microbes. It is most probable that the less-elaborated, restrictive adaptive immune response of fish and amphibians makes the preservation of phagocytosis an evolutionary advantage to B cells in their defence against pathogens. These findings support the idea that B cells evolved from an ancestral phagocytic cell type, providing an evolutionary framework for understanding the close relationship between mammalian B lymphocytes and macrophages.[a, n]

Mast cell degranulation releases histamine and other vasoactive mediators in response to allergens. Although this reaction is most often encountered in allergic reactions, it apparently evolved as a defense system against intestinal parasitism, such as tapeworm infestations.

The versatile immunoglobulin superfamily is evolutionarily ancient, is widely expressed, and is constitutive or long-term up-regulated. Immunoglobulin antibodies are released by activated B cells of the immune system, on which they also act as surface marker proteins. The enormous diversity of antibodies is attributable to the alternative splicing of VDJ recombination.

RAG1 and RAG2, the proteins that mediate VDJ recombination, are closely related to transposases, and it is believed that evolution of the vertebrate genome includes their entry as part of a Transib superfamily transposon.

Blood coagulation employs the same fundamental mechanism in all vertebrates, from the early diverging jawless fishes to mammals.[1]. It has been amply demonstrated that all groups of fish generate thrombin through pathways that:
● utilize vitamin K-dependent factors
● exhibit factor XIII-dependent fibrin cross-linking, and
● manifest a fibrinolysis inhibited by the same antifibrinolytic agents as mammals (1–3).

(Thrombin-generated fibrin coagulation has not been observed in nonvertebrate chordates or in other invertebrate animals.)

Such a convoluted pathway as the clotting cascade could not have evolved as a single event. Proponents of "intelligent design theory" attempted to monopolize on this fact in order to promote their claims that an intelligent designer (God) must be responsible for the so-called "irreducible complexity" of the coagulation cascade. (Behe is a little more cautious in his wording, but the implied argument is as stated above.) Just as for the claims of irreducible complexity for evolution of the eye and the bacterial flagellum, the argument has been both logically and scientifically refuted.

Scientists realized some time ago that a series of gene duplications must be responsible for the complex set of interactions observed in mammalian clotting. Sequence comparisons of serine proteases led to the suggestion that the contact system of clotting factors ( factors XI and XII, and prekallikrein) must have evolved more recently than some of the other clotting factors and thus would likely be absent in lower vertebrates (4).

The genome sequences (5) for the puffer fish, Fugu rubripes, along with that for the urochordate (sea squirt) Ciona intes (6) have enabled a direct comparison of two early diverging chordates. The genomes confirm that the main lines of the vertebrate clotting pathway were evolved during the less than a hundred million years between the last common ancestor of these two creatures. It is currently believed that 50–100 million years separate the appearances of urochordates (including the sea squirt) and vertebrates. During this interval, the machinery for thrombin-catalyzed fibrin formation was presumably 'concocted by gene duplication and the shuffling about of key modular domains'.[adapted from article]

Talk Origins Evolving Immunity . Evolution of the Immune System, Spring 2005 .

Sequence comparisons of the three homologous polypeptide chains that compose vertebrate fibrinogens (acute phase proteins) imply that the molecule evolved before the divergence of vertebrates and invertebrates. Computer comparisons of various fibrinogen-related sequences indicate that the sea cucumber proteins diverged before the beta-gamma gene duplication.
Presence of a vertebrate fibrinogen-like sequence in an echinoderm. [Proc Natl Acad Sci U S A. 1990]

Coelomocytes increased expression of ferritin mRNA after stimulation. In vertebrates, cytokines can cause changes in iron levels in macrophages. Similarly, echinoderm macrokines produced decreases in iron levels in coelomocyte supernatant fluids. These results suggest that echinoderm ferritin is an acute phase protein and suggest that sequestration of iron is an ancient host defense response in animals.
Evolution of the acute phase response: iron release by echinoderm (Asterias forbesi) coelomocytes, and cloning of an echinoderm ferritin molecule.[Dev Comp Immunol. 2002 Jan;26(1):11-26.]

tags [Immunology] [evolution] [immune system] [coagulation cascade] ["irreducible complexity"]

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