|Year : 2014 | Volume
| Issue : 1 | Page : 30-33
Pentraxins and immunity
Priya Nagar1, Deepak Viswanath1, Munivenkatappa Lakshmaiah Venkatesh Prabhuji2
1 Department of Pedodontics and Preventive Dentistry, Krishnadevaraya College of Dental Sciences and Hospital, Bangalore, Karnataka, India
2 Department of Periodontics, Krishnadevaraya College of Dental Sciences and Hospital, Bangalore, Karnataka, India
|Date of Web Publication||5-Sep-2014|
Department of Pedodontics and Preventive Dentistry, Krishnadevaraya College of Dental Sciences, Hunasamaranhalli, International Airport Road, Bangalore - 562157, Karnataka
Source of Support: None, Conflict of Interest: None
Pentraxin-3 (PTX3) is a multifactorial protein involved in immunity and inflammation, which is rapidly produced and released by several cell types in response to inflammatory signals. It may be suggested that PTX3 is related to periodontal tissue inflammation. Its salivary concentrations may have a diagnostic potential. Pentraxin-3 (PTX3) is an ancient family of multifactorial proteins involved in immunity and inflammation. They are rapidly produced and released by various types of cells when there are indications of inflammation. PTX3 is related to inflammation in the periodontal tissue and it can be suggested that salivary concentrations may be used for diagnosing the same.
Keywords: Ancient protein, complement system, immune response, pentameric structure
|How to cite this article:|
Nagar P, Viswanath D, Prabhuji MV. Pentraxins and immunity. J Oral Res Rev 2014;6:30-3
| Introduction|| |
Pentraxins are ancient proteins found in humans and are of two types ― C-reactive protein (CRP) and Serum Amyloid Protein (SAP). Pentraxins are known to have a pentameric structure of five subunits. These subunits consolidate to form a channel and their binding to their ligands is calcium-dependent. Pentraxins function as soluble, pattern-recognition molecules and their most important function is defense of the host against pathogenic bacteria. Pentraxins also interact with the complement system and fragment crystallizable (Fc) receptors to stimulate immune responses.
| History|| |
The discovery of CRP in man was achieved from the blood of a patient with severe Streptococcus pneumonia. ,, The protein was isolated the patient's blood during the infection. When the infection was in the acute phase, the protein was found in a high concentration, and was found to induce precipitation of pneumococcal cell-wall extracts, in the presence of calcium.
| Structure|| |
Pentraxins have two types of proteins C-reactive Protein (CRP) and Serum Amyloid Protein (SAP). Both proteins are composed of five tightly arranged subunits, in planar symmetry. The molecule appears like a doughnut-shaped ring when seen under a scanning electron microscope (SEM).  Both CRP and SAP have single pentamers.  This pentameric structure imparts a high degree of stability, and thus, offers resistance to the enzymatic attack.  The short pentraxins include the Serum Amyloid Protein (SAP) and C-Reactive Protein (CRP).
In recent times, another group of related proteins has been described, called the long pentraxins. They share the homology with pentraxins in the C-terminal region, but they have a long N-terminal domain that is unrelated to the short pentraxins. Generally the long pentraxins are produced locally in response to inflammatory stimuli, and can also help in wound healing.  The long pentraxins include PTX3 and many neuronal pentraxins.
Pentraxins and the complement
When it was found that pentraxins could help in the activation of a classical waterfall of the complement system, it was suggested that it was a significant natural function of the CRP, as the complement system has a wide range of activities in the natural shield, in addition to inflammation management. ,, It activates the classical cascade through the direct binding of C1q, a subunit of the C1 enzyme complex that activates the serum complement system. Each CRP pentamer has a single binding site for C1q and a minimum of two CRP molecules are required for C1 activation, similar to IgG. 
Complement activation by CRP is very similar to the complement activation by IgM or IgG immune complexes. However, more specifically, it is revealed that CRP activation does not  efficiently proceed to generation of the membrane complex, whereas, antibody activation does. CRP activates the early steps in the classical pathway by consumption of C1, C4, C2 and partial consumption of C3,and produces only minimal activation of C5 - C9, with no cell lysis. As C5a and C5b - 9 are the strongest inflammatory mediators produced during complement activation, this restricted activation favors opsonization without a strong inflammatory response. 
Pentraxins and protection from infection
C-reactive protein binding to S. Pneumoniae was the first ever indication that it might participate in protection from infection. ,, This was thought to be conducted by the activation of the complement system. Mice experiments showed that CRPtg mice had protection from Salmonella More Details typhimurium. The CRP recognized the pathogens by recognizing the phosphocholine indicated on the surface of S. pneumoniae, H. influenzae, and other organisms.  It was also found that CRP is also expressed in the respiratory tract and could be found in their secretions.  Thus, CRP may provide a barrier function, much like IgA, and a direct protective effect from respiratory tract pathogens.
The SAP binds to the ligands, activates the complement system, and enhances phagocytosis, thus both of them play an important role against S. pneumoniae. SAP is also known to inhibit the influenza viral infection. , It is found to inhibit the viral binding to hylauronic acid in a calcium-independent manner. , It is also found to be associated with the invasive C. albicans and also an amyloid associated with it in the gut. 
The C-reactive protein was also shown to bind the non-bacterial pathogens. It was found to bind avidly to Leishmania donovani (on the lipoglycan on the surface of L. donovani).  This binding between CRP and the non-bacterial pathogens induced cytokine production and phagocytosis or protected the host from infection.
It was also found that CRP had some interaction with malarial parasites. 
Pentraxins and monocytes and macrophages
The CRP and SAP preferentially bind to monocytes and neutrophils in the human's peripheral blood cells and opsonize targets for phagocytosis both directly through FcγR and FcαRI and indirectly through the activation of a complement.  This activation of the peripheral blood mononuclear cells (PBMC) by CRP and production of inflammatory cytokines has been reported by Ballou and Lozanski. 
C-reactive protein and neutrophil activation chemotaxis and phagocytosis
The CRP has an ability to opsonize both Gram-positive and Gram-negative pathogens. , Mortensen et al. have gone on to show that CRP and the complement acting together can induce phagocytosis of erythrocytes coated with the C-polysaccharide of S. pneumoniae (PnC).  The CRP also has an inhibitory effect on neutrophils, particularly on neutrophil chemotaxis. ,
Clinical use of C-reactive protein levels
The initial assays used to measure CRP in the circulation were relatively insensitive and for many years a positive value was used as an indication of inflammation or infection. CRP is an excellent marker of the acute inflammatory response and is used extensively for diagnosis and prognosis of rheumatological and other diseases. 
The CRP levels of 10 μg/mL up to 500 μg/mL can be seen in the acute phase response. About 20 years ago, highly sensitive assays were developed to detect baseline CRP levels in healthy individuals. These assays were said to measure high sensitivity (hs)-CRP.
The advent of the hs-CRP assay led to numerous studies that showed utility in individuals at risk for cardiovascular disease, metabolic syndrome, periodontal disease, and other chronic diseases associated with a low level of inflammation.
It has been noted that saliva, serum levels of PTX3, and interleukin (IL)-1β are seen in patients with generalized chronic periodontitis (CP) or aggressive periodontitis (AgP), and in periodontally healthy individuals. Studies showed that the serum and saliva data were similar in the CP and AgP groups. The saliva levels of IL-1β were significantly higher in the AgP and CP groups than in the controls (P < 0.05). The salivary PTX3 levels were similar in the CP and control groups. Significantly higher salivary concentrations of PTX3 were detected in the AgP group than in the control group (P < 0.05). The PTX3 levels in the saliva correlated with the plaque index and bleeding on probing in the CP group (P < 0.05). The serum and saliva PTX3 levels correlated with those of IL-1β in the AgP group (P < 0.05).
| Biomarkers|| |
Biomarkers are measurable and quantifiable biological parameters that have an important impact on clinical situations. The ideal biomarkers are associated with disease clinical endpoints in observational studies and clinical trials; sometimes they may be surrogate endpoints. Biomarkers must also be both independent and recognized, to be factors in the disease for which they are markers. Finally, biomarkers must have the ability to improve prediction beyond that of the traditional risk factors. Matsubara et al. 2011. 
PTX3 is a well-established cardiovascular biomarker C-reactive protein (CRP). , PTX3 also shares 98% identity with the tumor necrosis factor- (TNF-)stimulated gene 14 (TSG14). PTX3 has been successfully identified using differential screening of a cDNA library from human umbilical vein endothelial cells (HUVECs) stimulated by interleukin-1 beta, as well as by using the 2D-DIGE approach, to detect PTX3 in HUVECs stimulated by lysophospholipids.
Sleep apnea syndrome
The plasma PTX3 level is a good marker for response to treatment of patients with obstructive sleep apnea (OSA). It has been demonstrated that not only did patients with OSA express higher levels of plasma PTX3 than the matched control group, but also that continuous positive airway pressure (CPAP) therapy led to a significant reduction in the plasma PTX3 levels. 
Acute coronary syndrome (ACS)
The expression of PTX3 has been found to be increased in patients with acute myocardial infarction (AMI). It has been observed that patients with AMI, who were admitted to the Coronary Care Unit within hours of onset of symptoms, had increased plasma PTX3 over time. ,[ 33]
Biomarkers of vascular damage and albuminuria
The association between PTX3 and Urinary Albumin Excretion (UAE) may reflect a state of endothelial dysfunction (ED) (because vascular endothelial cells and macrophages are the main production sites of PTX3) rather than systemic inflammation. Indeed, adhesion molecules, which are considered to reflect ED and have elevated UAE are thought to represent a marker of generalized vascular dysfunction. ,[ 33]
PTX3 and proteinuria in type 2 diabetes
Development of albuminuria in patients with diabetes is believed to increase the risk for cardiovascular events through mechanisms that could involve low-grade inflammation, ED, and impaired insulin sensitivity. Studies show that in patients with type 2 diabetes, insulin sensitizers (thiazolidinediones) not only decrease UAE, but also enhanced insulin sensitivity and decrease the circulating TNF-α levels; also in these patients with type 2 diabetes and proteinuria, both CRP and PTX3 levels are independently associated with the degree of urinary excretion of proteins which suggests that these two members of the same pentraxin family (one short and one long) operate through different pathways, proving that CRP may reflect systemic inflammation, where PTX3 represents ED. 
Congestive heart failure
It was also observed that in heart failure with a normal ejection fraction (HFNEF), the plasma PTX3 levels were found to be increased. ,[ 33]
Heart valvular disease
In patients with aortic valve stenosis (AS) or regurgitation (AR), the expression of plasma PTX3 is increased. PTX3 was expressed predominantly in macrophage cells in the aortic valves of these patients. ,[ 33]
PTX3 involvement in cardiovascular diseases
The PTX3 levels are increased in patients with cardiovascular disease, in order to confer protection against cardiac tissue damage. For instance, PTX3-knockout mice showed exacerbated heart damage with a greater no-reflow area and increased inflammatory response, including increased neutrophil infiltration, a decreased number of capillaries, and an increased number of apoptotic cardiomyocytes. PTX3 has also been found to offer protection against atherosclerosis. PTX3 and the cell adhesion molecule P-selectin in the atherosclerotic lesions has recently been reported. 
| Conclusion|| |
Pentraxin is a progressive family of proteins represented by a cyclic multimeric structure. PTX3 is quickly produced and released by numerous cell types, especially by mononuclear phagocytes, endothelial cells, dendritic cells, and fibroblasts, in response to the primary inflammatory signals. PTX3 attaches itself with great inclination to the complement system C1q and preferred microorganisms, which include Pseudomonas and Aspergillus fumigatus. PTX3 activates the classical pathway of complement activation and facilitates pathogen recognition by macrophages and DCs.
The transcribed PTX3 protein is made of 381 amino acids and has a predicted molecular weight of 40,165 Da. It is formed of a carboxy-terminal 203 amino acid long pentraxin domain attached to an amino-terminal 178 amino acid long domain, distinct from other known proteins.
PTX3 behaves as an acute phase reaction protein. As the blood levels of PTX3 are usually low in normal conditions (about 25 ng/mL in the mouse, <2 ng/mL in humans), intensify quickly (peaking at six to eight hours after induction), and are significantly high (200-800 ng/mL) when in sepsis, endotoxic shock and other inflammatory and infectious situations are associated with the severity of the disease. In these situations, PTX3 is a quick marker for primary local activation of innate immunity and inflammation.
Pentraxin is an important biomarker in detecting various diseases like Cardiovascular disease, Diabetes, Vascular Diseases, and so on.
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