Although CD8 T REG have been documented in humans and mice [123–128], they have not been studied extensively, in part due to their low abundance (0.2 to 2% of CD8 T cells) in lymphoid organs. In comparison, the well-studied CD4 regulatory T cells, TREG, comprise 5–12% of CD4 T cell in the spleen. The FoxP3 + CD8 T cells and the TREG have overlapping and distinct functions. Both cells express CD25 and the transcription factor, FoxP3 a marker of the regulatory T cells. The osteoclast-induced FoxP3 + CD8 T-cells secreted cytokines that could suppress formation and activity by OCs. The FoxP3 + CD8 T-cells did not affect the survival of OCs, but FoxP3 + CD8 T-cells could directly act on mature OCs to suppress actin ring formation. The ability of OCs to induce FoxP3 + CD8 T-cells and the ability of FoxP3 + CD8 T-cells to subsequently regulate OC function establishes a bidirectional regulatory loop between these two cells in the bone marrow. Notably, the regulatory loop does not require the presence, in vitro, of proinflammatory cytokines. Indeed, the ability to isolate functional FoxP3 + CD8 T-cells from mice, in the absence of any inflammatory disease, indicates that these cells have a role in maintaining skeletal homeostasis in vivo .
Natural killer (NK) T cells are known to participate in the clearance of virus-infected, aberrant, or transformed cells . Moreover, NK cells are poised for a rapid release of cytokines and growth factors that might influence the initiation and development of immune responses mediated by T and B cells [131–133]. Moreover, the activation of a particular subset of NK cells, the invariant NKT (iNKT) cells, increases OC development, maturation, and activity .
NK cells can be detected in the inflamed synovial tissue at an early stage of the disease, and they constitute up to 20% of all lymphocytes in the synovial fluid (SF) of patients with established RA [135, 136]. Recent evidence shows that this CD56bright NK cell subset has an upregulated expression of several chemokine receptors and adhesion molecules that may participate in its preferential recruitment into the inflamed synovium  and enable the cells to engage and subsequently activate monocytes through a variety of receptor-ligand interactions [135, 138, 139]. NK cells in the SF of RA patients efficiently trigger formation of OCs from monocytes. In particular, NK cells express both M-CSF and RANKL, which are responsible for osteoclastogenesis, and both molecules are further upregulated on NK cells by IL-15 [140, 141].
Although the vast majority of circulating T-cells express TCR chains, a subset of T-cells expresses a different TCR, containing a gamma ( ) chain paired with a delta ( ) chain, to form a TCR heterodimer, and giving rise to a population of T-cells. T-cells represent only 1–10% of nucleated cells in the human peripheral circulation although their numbers are more abundant in tissues, in particular, epithelial tissues such as the skin, where T-cells may represent the dominant T-cell population . T-cells are dissimilar to T-cells in that their function is largely innate-like rather than adaptive and TCR specificity is directed almost exclusively towards nonpeptide antigens. They have been implicated in responses to inflammation, allergy, autoimmunity, infectious disease , and certain hematological tumors [142, 143]. They express growth factors important for tissue regeneration, such as fibroblast growth factor  and connective tissue growth factor,  that are critical for wound and skeletal fracture healing. Rather than representing a single population, T-cells have been found to be quite heterogeneous. Although found only in humans and higher primates, V 9V 2 T-cells are a major subpopulation of T-cells and are unique in their recognition of low-molecular-weight nonpeptide antigens. Recently, Kalyan et al. demonstrated that these unique innate T cells are lost in osteoporotic patients on amino-bisphosphonate treatment, and this loss is related to the potency of the systemic dose and the length of time on therapy and the diagnosis of osteonecrosis of the jaw [145, 146].
In addition to this immune function, B cells have a close and multifaceted relationship with bone cells . B cells differentiate from hematopoietic stem cells (HSCs) in supportive niches found on endosteal bone surfaces. Cells in the osteoblastic lineage sustain HSC and B cell differentiation in these niches. B cell differentiation is regulated, at least in part, by a series of transcription factors that function in a temporal manner. While these transcription factors are required for B cell differentiation, their loss causes deep changes in the bone phenotype. This is due, in part, to the close relationship between macrophage/OC and B cell differentiation. While the role of B cells during normal bone remodeling appears minimal, activated B cells play an important role in many inflammatory diseases with associated bony changes. In particular, B cells [148–150] and B-cell-derived plasma cells in multiple myeloma (MM) have been reported to have the potential to support osteoclastogenesis , possibly via direct expression of RANKL , decoy receptor 3 (DcR3) , or as an indirect consequence of IL-7 secretion [154, 155], a potent stimulator of bone resorption in vivo . Malignant B-cell-derived plasma cells in MM produce also different cytokines inhibiting OB differentiation, such as sclerostin and DKK1 [151, 157, 158]. Moreover, B lymphopoiesis is stimulated during estrogen deficiency  while estrogen treatment downregulates B lymphopoiesis but upregulates immunoglobulin production . B-lineage cells have consequently been suggested to play a role in ovariectomy-induced bone loss . Interestingly, immature B cell populations expressing the marker B220 have been suggested to transdifferentiate along the OC pathway in vitro  providing a potential enhanced source of OC precursors and an explanation for a role of B-lineage cells in ovariectomy-induced bone loss. After the discovery of RANKL as the key osteoclastogenic cytokine, expression of this factor by B-lineage cells (B220+ cells, which in the bone marrow represent multiple populations of early B-cell precursors, immature B cells, and mature B cells) has been reported to be more abundant in ovariectomized mice than in sham-operated mice . RANKL from B cells isolated from the bone marrow of estrogen-deficient postmenopausal women has been demonstrated to secrete RANKL , providing a plausible mechanism for a role of B cells in estrogen deficiency-bone loss. Peripheral blood B cells inhibit OC formation in a human in vitro model of osteoclastogenesis, in part by secretion of TGF ,  a cytokine that induces apoptosis of OCs [164–166] and that is reported to stimulate OPG production . Depletion of B cells in vivo also aggravates bone loss in an animal model of periodontitis, suggesting that B cells may act to limit bone resorption under certain pathological conditions .
Recently, however, to better address this issue, Onal et al. made use of a state-of-the-art conditional B cell RANKL KO mouse, to reevaluate the role of mature B cells in ovariectomy-induced bone loss. This high-sensitivity model did indeed reveal a small contribution of mature B cells to ovariectomy-induced bone loss as mice lacking RANKL in B lymphocytes were partially protected from the increase in OC numbers and bone loss caused by ovariectomy in cancellous bone, although not in cortical bone, in the conditional KO mice .
The prominent role of B cells is also documented in an animal model of HIV-1 infection. In particular, it has been recognized as strong defect in skeletal homeostasis that led to a significant decline in bone mineral density and in bone volume. These alterations in skeletal mass were consistent with significantly elevated OC numbers and bone resorption, a consequence of a significant decline in B cell OPG production, compounded by a significant increase in B-cell production of RANKL. Production of RANKL is indeed an established property of activated B cells [170, 171] and of B-cell precursors . This imbalance in the RANKL/OPG ratio was favorable to osteoclastic bone resorption and was likely further exacerbated by a dramatic increase in the number of OC precursors . Clinical studies to ratify these changes in humans are currently underway.
Furthermore, B-cell to T-cell crosstalk may regulate B-cell production of bone-active cytokines, because B cells suppress osteoclastogenesis when activated by Th1 cytokines while promoting osteoclastogenesis when stimulated with Th2 cytokines . In vitro ligation of the costimulatory molecule CD40 on human tonsil-derived B cells with an activating antibody is reported to stimulate B-cell OPG production . Physiologically CD40 interacts with its cognate ligand, CD40 ligand (CD40L), a molecule expressed on activated T cells during antigen presentation by antigen-presenting cells such as B cells, macrophages, and dendritic cells , and acts in priming of naive CD8 + cells .
Moreover, both T cells and B cells are involved in the process of basal bone turnover. In addition to the well-documented roles of lymphocytes in bone destruction under pathological conditions, both T and B cells cooperate to play a critical role in limiting basal bone resorption in vivo. This protective effect is centered on a mechanism involving the production of OPG by B-lineage cells, and augmented by T cells, via CD40/CD40L costimulation .
Dendritic cells (DCs) are highly differentiated antigen-presenting cells (APCs) that play a key role in the initiation and regulation of T cell immunity to pathogens and tumors while at the same time preventing immune responses against self-tissues or environmental antigens . Under normal conditions, DCs are rarely localized in the bone proper or adjacent stroma, and they do not seem to contribute to bone remodeling, as DC-deficient animals have no skeletal defects . On the other hand, it has been clearly documented that active lesions of rheumatoid arthritis and periodontitis harbour both mature and immature DC located in different compartments of the affected synovial and periodontal tissues surrounded by bone [181–186]. Interestingly, at active disease sites of rheumatoid arthritis and periodontitis, DCs can form aggregates with T cells in inflammatory foci, whereby they can interact through RANK-RANKL signaling in vivo, and they have been described as indirect players influencing inflammation-induced bone loss through regulating T cell activity [181–187].
Recently, Rivollier et al.  showed that human peripheral blood Mo-derived DCs can transdifferentiate into OCs in the presence of M-CSF and RANKL in vitro, suggesting that DCs might directly contribute to osteoclastogenesis. Alnaeeli et al. tested whether DC/T cell interactions can support DDOC development by in vitro cocultures using pure CD11c+CD11b−DC subset (lacking classical OC precursors [189, 190]) derived from total bone marrow (BM) cultures in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin IL-4 . The results suggest that (1) murine CD11c+DC can develop into functional OCs (DDOCs) during immune interactions with CD4 + T cells and microbial products or protein Ags in the bone environment and (2) DDOCs can induce bone resorption after adoptive transfer onto NOD/SCID mouse calvarias in vivo . These findings indicate a potentially critical contribution of CD11c+DC subset(s) to elevated osteoclastogenesis associated with inflammatory bone disorders where they act not only as potent APCs for immune activation and regulation but also as direct contributor to bone destruction. DCs also promote hyperactive osteoclastogenesis in MM bone disease [192, 193] because their number is higher within the erosive lacunae. In addition, they may undergo OC-like transdifferentiation following stimulation by the RANK-RANK-L . Additionally, mature DCs may drive, within the tumor site, the expansion of a Th-17 clone leading to IL-17 overproduction that enhances osteoclastogenesis .
Neutrophil granulocytes are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system. Neutrophils are normally found in the blood stream. During the beginning (acute) phase of inflammation, particularly as a result of bacterial infection, environmental exposure  and some cancers [197, 198] neutrophils are one of the first responders of inflammatory cells to migrate towards the site of inflammation. The sites of bony lesions in humans and in animal models show massive infiltration of the prototypic inflammatory cells, neutrophils. Neutrophils are also implicated in human periodontitis , as well as several arthritis animal models [200–202]. Of note, although traditionally considered to be short-lived cells with limited synthetic capacity, activated neutrophils have been shown to synthesize considerable amounts of proteins and lipids that participate in the inflammatory process [203, 204]. In human neutrophils from inflammatory sites expressed high levels of RANKL . Human, as well as murine, neutrophils strongly upregulate their expression of membrane RANKL after LPS stimulation and thus have the capacity to activate osteoclastic bone resorption through neutrophil-OC interactions . The osteoclastogenic effect of neutrophil RANKL, demonstrated with human- and murine-activated neutrophils (purity > 95%), was reproduced with purified neutrophil membranes and fixed neutrophils, but not with culture supernatants of activated neutrophils in which no secreted RANKL was detected. Thus, RANKL expression in neutrophils differed from that in activated CD3 + lymphocytes, which express both cell surface and soluble RANKL [207, 208]. Moreover, neutrophils can affect OB functions in children on chronic glucocorticoid therapy as well as in tophaceous gout leading to decreased bone formation and increased bone resorption [209, 210].
Over the past two decades extraordinary advancement has been done in understanding the crosstalk between the bone and immune system in physiological and pathological conditions. Although numerous data arise from animal models, exciting data from human studies are emerging and as a consequence the first biological drugs targeting cytokines released from immune cells are emerging as alternative therapeutic management for inflammatory bone disease, such as arthritis and osteoporosis. However, despite the advancement made, further studies needed to elucidate the cross-talk between the bone and immune system.
Do you feel like you’re always getting colds, skin rashes, headaches, fatigue or sinus infections? Well, maybe you need to do a cleanse that focuses on boosting your immune system, so your body can defend itself better from bacteria, viruses, parasites and fungi. A good time to start thinking about boosting your immune system is before flu season comes around, or before any airplane travel.
Our immune system is supposed to protect us from these everyday illnesses, but our lifestyle choices can weaken this protective shield, leaving us vulnerable to disease and infections. A lot of the food we ingest is man-made, processed junk that put stress on your body and immune system. We should really be focusing on fresh, natural food. By cleansing out some bad lifestyle habits and junk food you can have your body fighting off every germ that comes your way!
Here are a few foods to eat and foods to avoid while you’re doing an immune system cleanse. Remember to be realistic – cutting out 100 percent of the bad stuff is probably not going to happen! However, if you try to stick to the plan for 2 weeks and work out a diet and lifestyle that work for you, then you’ll start to see some real improvements to your health.
These are the foods and lifestyle choices that actually weaken your immune system.
Both alcohol and coffee lower the amount of white blood cells in your bloodstream. This weakens your body’s defenses against illness. They also impair the body’s absorption of vital nutrients, weakening the body and making it more susceptible to illness.
Cigarettes contain arsenic, cadmium, formaldehyde, to name just a few of the toxic chemicals that enter your system whenever you light up. All of these will impair your immune function – irritated lungs are much more vulnerable to infection.
Too much sugar can also suppress your immune system. Avoid sugar, honey, syrup, chocolate, and check labels for anything ending in “ose”. Avoid white flour and white flour products too – they affect the immune system in much the same way.
If you have a sweet tooth, you might think this is going to be an impossible task, but stick to it for a coupe of weeks and your cravings will go away. You can have a piece of fruit to curb your craving, but stay away from artificial sweeteners as they are very toxic, even worse than sugar.