The effects in the ocular environment are pronounced. Signs include swelling, redness and exudate production. There is also extreme sensitivity to light photophobia.
They are used reduce joint pain and swelling due to arthritis. Blockers interact directly with TNF to prevent binding and thus actions on cells. It is a primary treatment for rheumatoid arthritis [13]. Anti-TNF agents of all types have a number of side effects include redness and burning at the injection site. Coughing, headaches, nausea, weakness, and general malaise are also symptoms of the treatments. However, when used they are effective in reducing physiological stress due to excess TNF levels, that may be systemic or occur locally.
Tumor necrosis factor may be thought of as first among equals as relative to its relationship to other cytokines. This may be considered to be so for a variety of reasons including the time at which it is stimulated, the mode of action of the cytokine itself, and the cells types involved and the pathologies that results.
There are a number of therapies that have been developed and are currently used in clinical practice which act as TNF antagonists directly. These have greater or lesser degrees of therapeutic success and also side effects depending on the individual patient. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Read More. Special Issues Frequently Asked Questions. Links Advanced knowledge sharing through global community… Read More. Take a look at the Recent articles. The role of proinflammatory cytokines in the pathogenesis of fever has been discovered at the end of the s and the beginning of the s, with the purification of IL-1 and demonstration of its pyrogenic properties [ 1 ]. Injection of IL-1 into experimental animals has potent pyrogenic effects, and administration of an excess dose of IL-1 receptor antagonist IL-1Ra can prevent fever [ 22 ].
In humans, IL-1 appears to be the most potent pyrogenic cytokine. The febrile response increased in magnitude with increasing doses [ 26 , 27 ], and fever was reduced by administration of indomethacin [ 28 ].
More controversial are the data regarding the role of IL-1 in mediating fever induced by lipopolysaccharides LPS. The reasons for these discrepancies are unclear. TNF is a proinflammatory cytokine that shares many biologic properties with IL-1 [ 35 ]. TNF injection induces a typical fever in rabbits that is indistinguishable from IL-1 [ 3 ]. Moreover, TNF induces a second fever peak 3—4 h after challenge, which is suggested to be mediated through induction of endogenous IL-1 production [ 1 , 3 ].
Recombinant human TNF is highly pyrogenic in humans, and the fever induced is rapid and associated with generalized malaise and joint pain [ 1 ]. IL-6 is a cytokine initially described as a potent acute-phase protein inducer [ 38 ].
It has been shown that IL-6 elicited fever when injected into rabbits and that IL-6 concentrations were correlated with fever in human patients with burns [ 39 ]. Although one of the most potent proinflammatory properties of IL-6 is the stimulation of PG synthesis, IL-6 induction of fever in rabbits requires to fold higher amounts of IL-6 than of IL-1 [ 1 ].
Figure 1 depicts this cytokine cascade of fever induction, in which initial stimulation of IL-1 and TNF by bacterial products induces secondary synthesis of IL-6, with subsequent induction of PG synthesis in the CNS and fever. The cascade of cytokines acting as endogenous pyrogens in the pathogenesis of fever induced by bacterial products such as lipopolysaccharide LPS.
PGE 2 , prostaglandin E 2. IFNs were described as antiviral substances, with potent immunostimulatory activities such as enhanced expression of class I and II major histocompatibility complex antigens and stimulation of natural killer activity. In addition to the proinflammatory cytokines acting as direct EP, other endogenous inducers can have indirect pyrogenic properties through their capacity to induce synthesis of EP.
Infusion of recombinant IL-2 into humans induces fever that starts 3—4 h after injection [ 47 ]. However, the fact that by the time of fever, the IL-2 concentrations in the patients are low [ 48 ], and considering the capacity of IL-2 to induce production of IL-1 and TNF [ 49 , 50 ], together suggest that the pyrogenic properties of IL-2 are mediated through induction of IL-1 and TNF. Other potentially important endogenous inducers are granulocyte-macrophage-colony stimulating factor, immune complexes, and uric acid crystals, all molecules with pyrogenic potential through their capacity to induce production of IL-1 and TNF [ 51 ].
An important role as endogenous inducer of fever may be reserved to the complement system. On the one hand, this is due to cytokine stimulation by the complement factors C3a and C5a [ 52 , 53 ]. On the other hand, the fever response after LPS challenge is blocked in guinea pigs with low complement levels obtained by pretreatment with cobra venom factor, suggesting a direct role of the complement system in the induction of fever [ 54 ]. A key event in the induction of fever in the classical model of pathogenesis described above is the release of pyrogenic cytokines into the bloodstream to mediate the signal leading to a febrile response from the site of inflammation to the thermoregulatory center in the hypothalamus figure 2 , panel I.
However, there are aspects in the induction of fever that contradict this dogma. Experimental studies have shown that after LPS injection, fever precedes the appearance of cytokines in the circulation [ 55 ]. Clinical studies have failed in finding detectable levels of EP in specific patient groups with febrile conditions such as typhoid fever [ 56 ], fever of unknown origin [ 57 ], and Pneumocystis carinii pneumonia [ 58 ].
In severe infections with septic shock, proinflammatory cytokines are detected in the circulation only for a short time compared with the period the duration of fever [ 59 ]. In addition, release of high amounts of anti-inflammatory cytokines has a strong inhibitory effect on the action of pyrogenic cytokines.
Moreover, continuous infusion of cytokines in animals leads to transient rather than ongoing fever [ 60 ]. Although it is conceivable that a combination of cytokines acting at very low concentrations may provide the signal for the induction of fever or that as-yet unidentified pyrogenic cytokines act as circulating EP, there are data in the literature that suggest that alternative pathways besides circulating pyrogenic cytokines may efficiently induce fever in response to peripheric stimulation.
Panel I , the classical model for the induction of fever, in which circulating pyrogenic cytokines represent the key event. Panels II and III , an alternative model in which local production of proinflammatory cytokines at the level of infected tissues stimulates either the release of secondary mediators into circulation panel II or primary vagal terminals in the liver panel III.
The secondary mediators e. The cytokines are either released upon adherence to the endothelium by activated monocytes in which expression of pyrogenic cytokines mRNA is high panel IV or produced directly by endothelial cells stimulated by exogenous pyrogens circulating in the bloodstream panel V. Panel VI , the possible involvement of cell-associated cytokines on the membrane of activated monocytes for the stimulation of endothelial cells in OVLT. Production of cytokines at the tissue level has been suggested as an alternative pathway for the induction of the signal leading to fever, rather than in circulation.
Local production of proinflammatory cytokines in the infected tissues may induce release of secondary mediators with pyrogenic properties figure 2 , panel II. One possible candidate for this role may be soluble type II phospholipase A 2 [ 61 , 62 ]. However, the arguments for its involvement in the pathogenesis of fever are circumstantial, and infusion of recombinant phospholipase A 2 into rabbits have failed to induce fever [ 64 ].
An additional mechanism through which local cytokine production may induce fever is through stimulation of vagal terminals in the liver [ 20 ] figure 2 , panel III. These signals are transported through vagal afferent fibers and noradrenergic neurons in the brain stem, reaching the OVLT, where the release of noradrenaline induces PG release and fever [ 20 ].
In addition to production and release of proinflammatory cytokines in the peripheral tissues and in the circulation, release of these mediators at the level of the OVLT endothelium may also represent an important mechanism in the induction of fever. In this model, activation of monocytes may result in little or no production of cytokines. However, the activated monocytes may subsequently enter the bloodstream and adhere to the endothelium in the circumventricular organs [ 67 ], where release of EP from either the monocytes themselves or from endothelial cells can induce the signal leading to fever figure 2 , panel IV.
Indeed, activated monocytes are present in the bloodstream with low or absent circulating cytokine concentrations [ 68—70 ], and production of cytokines by perivascular cells in the circumventricular organs has been demonstrated [ 71 ].
An important pathway through which exogenous pyrogens such as LPS may induce fever is through direct induction of proinflammatory cytokine production by endothelial cells in the circumventricular organs figure 2 , panel V. An additional important factor for the ligand-receptor interaction is a plasma factor, LPS-binding protein, which transfers LPS from the circulating micellae to the receptor complex [ 74 ].
Interestingly, an intracytoplasmic domain of the TLRs is homologous to a segment of the IL-1R type I [ 75 ], resulting in striking similarities in the intracellular signals induced by LPS and IL-1, respectively figure 3. In terms of fever, injection of a small amount of LPS into rabbits induces a monophasic fever identical to that observed after IL-1 or TNF [ 11 ], probably through intermediary production of IL-6 [ 40 ].
These findings provide the theoretical basis for the hypothesis that certain bacterial products can circumvent the need of stimulating a circulating EP in order to be able to induce fever [ 7 ]. Thereafter, the signal transduction pathway is very similar to that of the IL-1 receptor. In addition to inducing secretion of soluble forms of proinflammatory cytokines, live bacteria and their products also stimulate the synthesis of cell-associated cytokines, which are known to be highly biologically active [ 76 , 77 ].
It is therefore tempting to speculate that activated monocytes in the circulation, expressing high levels of membrane-bound cytokines, are able to activate endothelial cells in the OVLT and to induce fever in the absence of detectable concentrations of secreted cytokines figure 2 , panel VI.
Fever is an adaptive mechanism that plays an important role in the survival of the host during infection with pathogenic microorganisms. Studies performed in the last century, and especially in the last few decades, have greatly contributed to the understanding of this complex process and the mechanisms responsible for its induction. Circulating proinflammatory cytokines acting as EPs play a pivotal role in transmitting the signal responsible for inducing a febrile response from the peripheral tissues to the CNS.
However, additional mechanisms may have an important role in the pathogenesis of fever, including local production of cytokines in the tissues, release of proinflammatory cytokines at the CNS level, direct induction of fever by exogenous pyrogens such as LPS, and membrane-bound cytokines acting as cell-associated EP [ 64 ]. It is possible, even probable, that different combinations of these mechanisms are involved in certain situations. In most cases, an affected person inherits the mutation from one affected parent.
Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family. Genetics Home Reference has merged with MedlinePlus. Learn more. The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health. Tumor necrosis factor receptor-associated periodic syndrome.
From Genetics Home Reference. Description Tumor necrosis factor receptor-associated periodic syndrome commonly known as TRAPS is a condition characterized by recurrent episodes of fever.
Frequency TRAPS has an estimated prevalence of one per million individuals; it is the second most common inherited recurrent fever syndrome, following a similar condition called familial Mediterranean fever. Inheritance This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
Genetic and Rare Diseases Information Center Tumor necrosis factor receptor-associated periodic syndrome. Research Studies from ClinicalTrials. Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes. Arthritis Rheum. Arthritis Res Ther.
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