Article Summary
Introduction
Breast implants are under recent scrutiny owing to concerns about their potential for inducing immunological diseases, namely breast implant-associated anaplastic large cell lymphoma and breast implant illness. However, the impact of silicone on biologic systems remains unclear. Therefore, we performed a systematic literature review to evaluate the information available on silicone breast implants and their effect on one arm of the adaptive immune response—B lymphocytes and antibody formation.
Methods
We conducted a systematic review in EMBASE/PUBMED in accordance with the PRISMA guidelines, with search entry terms requiring discussion of silicone and immunity. The initial review returned 1079 citations. Manual screening was performed to include studies that were specific to the humoral response after exposure to silicone. Secondary full text review was performed. The extracted data included animal models and findings pertinent to B cells/antibodies in response to breast implant silicones.
Results
In total, 39 studies on B cells/antibodies and breast-implant-associated silicones were identified. Among them, 23 studies were in humans, 14 in animal models, and 2 were in vitro. Common themes included identification of antisilicone antibodies in women with breast implants, anticollagen antibodies, presence of activated B cells or immunoglobulin G in implant capsules, and sensitization of lymphocytes to silicone in vitro.
Conclusion
Despite controversial findings in the literature, there is evidence that silicone breast implants activate B cells in the breast implant capsule and may have systemic effects on the production of autoantibodies and/or sensitization of B lymphocytes to silicone. Further research is needed on how breast implants impact other arms of the immune system to understand their long-term biological impact.
Keywords: Silicone, Breast, Implants, Immune system, B cells, Lymphocytes
Introduction
Silicone has been used in medical devices for over 50 years now. Despite this, its safety in relation to breast implants has long been questioned.1,2 Although silicone is considered chemically inert, several phenomena have implicated that silicone breast implants are not biologically inert. Breast implant illness is one of the several names given to a complex of symptoms observed in some women with breast implants.3, 4, 5 These symptoms include fever, arthralgia, hair loss, fatigue, chronic pain, headache, chills, and body ache, that are collectively reminiscent of several autoimmune disorders. It is thought that the foreign body response against the silicone implant activates the immune system against self, leading to autoimmune like symptoms, although there is no consensus among the medical community as to whether this is a legitimate diagnosis. Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is another disease observed in association with breast implants that results from T cell activation and proliferation in the capsule.6 Though it was initially considered rare, approximately 1400 cases are currently reported worldwide.7 Recently, the Food and Drug Administration (FDA) announced a link between breast implants and various B cell lymphomas.8,9 Unlike BIA-ALCL, breast implant-associated B cell lymphomas (BIA-BCL) are a heterogenous group of malignancies, comprising various types of B cell lymphomas (approximately 10 different types have been described). Evidently, the implant—whether it is the silicone shell, inner gel, or some other aspect of the foreign body itself —has the ability to activate multiple arms of the immune system.
Most literature surrounding these concerns has focused either on the T cell response (given ALCL is a T cell malignancy) or clinical symptoms of breast implant illness. The basics of B cell-mediated responses to breast implants has largely been only of secondary interest. Our group, however, has found that women with breast implants have elevated antibody responses to certain breast proteins (mammaglobin-A and MUC-1).10,11 We also identified elevated B cell markers in the breast tissue of women with implants compared to those without.11
Given that breast implant illness mimics autoimmune disease (which is often secondary to self-antibody production) and considering the increasing incidences of BIA-BCL, we sought to summarize what is known about the basics of breast implant mediated B cell activation. Our goal was to identify studies that examined the effect of silicone breast implants on B cell immune responses at the cellular and molecular level (rather than clinical symptomatology, which has been more extensively described). Thus, we performed a systematic review to summarize the literature on breast implant-associated B cell and humoral responses. With this review, we aimed to help increase the understanding about the biological impact that silicone breast implants may have and shed light on areas where further research is needed.
Methods
Literature Search
A literature search was conducted on May 28, 2022 in EMBASE and PUBMED for relevant articles with abstracts in English. The search strategy was developed in conjunction with a research librarian from the Galter Library at the Feinberg School of Medicine at Northwestern University. The literature search and subsequent analysis were conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses guidelines. Eligible studies were limited to articles in English language and required to examine the effects of silicone on immune cells in cell culture or animal models. Study selection underwent 2 levels of review by 2 independent researchers. Studies on immune reactions to silicone in specific organs other than the breast were excluded (for instance, several papers reported ocular inflammatory responses to silicone-based contact lenses and nasal capsular contracture around silicone-based nasal implants). The specific search entry terms were “Silicone,” “Silicones,” or “Breast Implant” in the title or abstract. The journal article also was required to include “Immune response,” “Immune system,” “Immunity,” “Adaptive immunity,” “Cellular immunity,” “Humoral immunity,” “Innate immunity,” “Mucosal immunity,” or “Active immunity,” in the title, abstract, medical search term heading, or as a major topic of the article. We included articles with “contracture” and “capsule.”
Titles and abstracts were screened for the following exclusion criteria: publications such as brief communications, correspondence, discussions, letters, conference or lecture manuscripts, case reports, and reviews; publications containing only abstracts; novel modifications of surgical technique; and outcomes about only a specific high-risk population. Additional search methods included a manual review of reference lists of the relevant studies specific to B cells. Details collected from the papers included author, year of publication, cell type or animal model, immune cell characteristics, sample size (for animal models), relevant statistical results, and p-values.
Results
Our search retrieved a total of 1096 articles. Reviewing the initial number in their entirety for inclusion and exclusion criteria resulted in the exclusion of 1065 results. Thus, 39 studies were finally included in this systemic review: All were discovered through computer search and no additional articles were found after reviewing relevant citations (Figure 1). Twenty-three papers used data from human patients, 14 papers were focused on in vivo animal models, and 2 studies were conducted using in vitro human cell culture models (one of them included both in vitro and animal data). Among the studies involving patient data, 4 examined the immune environment in the peri-implant or capsular tissue. These studies represented the local immune response. Nineteen studies from the 23 patient studies described B cell response from serum. These represented the systemic B cell response to silicone. Common themes of studies on the local immune response within the capsule show that intracapsular lymphocytes are predominantly T cells, with B cells representing a minority. The B cells can form reactive germinal centers and plasma cells (activated antibody secreting B cells). With regard to peripheral B cell-mediated immunity, several studies have identified elevated antisilicone and antiself antibodies. Animal models have demonstrated that it is possible for silicone to act as an adjuvant and induce B cell-mediated responses. Notably, a number of studies have reported negative findings (with no indication of B cell-mediated immunity being upregulated or different compared to women without breast implants). In total, 10 studies were identified with negative findings.
Figure 1.
Search strategy. Attrition diagram depicting the search strategy, including manual and computer search results.
The final list of included studies along with a summary of their findings are presented in Table 1.
Table 1.
Retrieved studies and summarized findings. The relevant findings from each of the retrieved studies included in review are documented. Studies are categorized by the model organism, immune environment, and control group used.
| Author (Year) | Model Organism | Immune Environment | Control Group | Major findings |
|---|---|---|---|---|
| Abbondanzo (1999) | Human | Capsular tissue | Not specified |
|
| Bar-Meir (1995) | Human | Serum | Implant-naïve | Compared to 134 control patients, silicone implant patients (n = 116) with rheumatic complaints:
|
| Bekerecioglu (2008) | Human | Capsular tissue | Implant-naïve | SBIs (n = 15) induced:
|
| Brantley (1990) | Rat | Spleen | Placebo-injected, implant-naïve | At 8 months:
|
| Bridges (1993) | Human | Serum | Symptom-free women with SBIs (n = 12), fibromyalgia patients without SBIs (n = 174) | Among the 156 patients with SBI with rheumatic complaints:
|
| Brunner (1996) | Human | Serum | Saline-filled implant | At up to 10 years of follow-up:
|
| Ciapetti (1995) | Human | Serum | Implant-naïve | At up to 10 years of follow-up (mean = 4.83):
|
| Cuellar (1995) | Human | Serum | None | 813 individuals with SBIs were tested for ANAs:
|
| De Jong (2002) | Human | Serum | Implant-naïve | No difference in the prevalence of anti-polymer antibodies between silicone breast implant and implant-naïve patients. Likewise, clinical symptoms did not correlate with anti-polymer antibody levels. |
| Ellis (1997) | Human | Serum | Implant-naïve | Silicone implants (n = 26) studied for response against connective tissue proteins and to compounds common to silicone prostheses:
|
| Fracol (2021) | Human | Serum | Implant-naïve | After an average of 7 to 10 years after implant:
|
| Granchi (1995) | Human | Serum | Implant-naïve | After 1 year of implantation:
|
| Habal (1980) | Mouse | Spleen | Implant-naïve, implant composed of other biomaterials (e.g., polyurethane) | After 1 month, splenic lymphocytes from mice receiving silicone implants showed:
|
| Haddad (2007) | Rat | Peri-implant tissue | Implant-naïve | At up to 180 days:
|
| Heggers (1983) | Guinea pig | Peri-implant tissue, lymph nodes | All received implant. Control did not receive silicone injection pre-implant | After 4 weeks:
|
| Karlson (1999) and Karlson (2001) | Human | Serum | Implant-naïve | After over 10 years postimplant (mean of 11.86 years):
|
| Klykken (1996) | Mouse, rat | Serum | Placebo-injected | IgM and IgG antibody responses were equivalent between silicone gel-implanted and control animals. No adjutancy was noted in the models tested. |
| Meza Britez (2012) | Human | Capsular tissue | Textured implants, implants without contracture | Periprosthetic breast implant capsules, textured and smooth (n = 40) showed:
|
| Naim (1995) | Rat | Serum | PBS-injected | After 108 days from injection of silicone gel from commercial breast implants:
|
| Naim (1993) | Rat | Serum | PBS-injected | At up to 56 days postimmunization:
|
| Naim (2000) | Mouse | Serum | PBS-injected | Up to 6 months post silicone exposure:
|
| Naim (1995) | Rat | Serum | PBS-injected | Silicone gel could significantly heighten the antibody response, against:
|
| Narini (1995) | Sheep | Lymph nodes | Saline-injected | At one month after silicone gel injection:
|
| Peters (1994) | Human | Serum | Implant-naïve | Among the 200 patients with SBI:
|
| Prantl (2008) | Human | Serum | Implant-naïve | After an average of 34 (SD 11) months of exposure to silicone breast implants:
|
| Press (1992) | Human | Serum | None | Among the 23 patients with SBI:
|
| Rhie (1998) | In vitro | Spleen | Non-coated Petri dishes | After 3 days of silicone exposure:
|
| Rodriguez (2008) | Rat | Implant Exudate | Empty implant | After 14 days postimplant exposure:
|
| Rohrich (1996) | Human | Serum | Implant-naïve | At an average of 6 months postimplant:
|
| Sanger (1995) | Human | Capsular tissue | n/a | Chronic presence of silicone implant (time not specified):
|
| Schuler (1978) | Rat | Serum | Implant-naïve | After 16 days of silicone implant exposure:
|
| Stern (1972) | Rabbit | Serum | Nonsilicone exposed |
|
| Tenenbaum (1997) | Human | Serum | Implant-naïve | SBI recipients had higher prevalence of positive anti-polymer antibodies than healthy and autoimmune disease patients that were implant-naïve. Antibody levels correlated with more severe clinical symptoms. |
| Teuber (1993) | Human | Serum | Implant-naïve | After an average exposure to silicone breast implants for 13.5 years (SD 5.3 years):
|
| Vojdani (1994) | Human | Serum | Implant-naïve |
|
| Wolf (1993) | Human | Serum | Implant-naïve | After exposure to silicone:
|
| Zandman-Goddard (1999) | Human | Serum | Asymptomatic SBI patients | Symptomatic (n = 116) and asymptomatic (n = 86) women with SBIs had elevated anti-SSB/La and anti-collagen II antibodies.
|
| Zeng (2015) | In vitro, mouse | Serum | None (used stiff vs. soft biocompatible organosilicon elastomer) | After 3 days of exposure to polydimethylsiloxane (PDMS) surfaces:
|
ANA, antinuclear antibody; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; LPS, lipopolysaccharide; SBI, silicone breast implant.
Discussion
How the Body “Sees” The Foreign Body Implant
There are 2 ways by which the body “perceives” the breast implant: first, directly through the outer silicone shell and second, through particulate debris shedding (also known as silicone gel bleed).
Host immune cell responses to the outer silicone shell are the primary drivers of the initial foreign body response and can result in capsule formation.12 This foreign body response is a highly programmed cascade of events, with each stage defined by specific subsets of immune cells, proteins, and surface interactions. It begins with self-protein deposition on the implant surface, within nanoseconds of its placement in the breast.12 The most common proteins found adsorbed to the silicone surface include fibronectin, immunoglobulin G (IgG), complement, and fibrinogen.12 These proteins then activate the coagulation (fibronectin) and complement (IgG) cascade. The end result of these cascades is an increase in vascular permeability and exposure of integrin binding sites on adsorbed proteins, which signal macrophages and leukocytes to make their way into the peri-implant space and interact with the protein adsorbed surface.12
Beyond interacting with the implant through its outer shell surface, the immune system can also perceive the implant through silicone gel bleed.13 Macrophages are considered the “sentinel cell” of the immune system and one of the key immune cells found in implant capsule. Silicone debris is taken up by resident macrophages, which subsequently fuse to form multinucleated giant cells and/or granulomas. Silicone debris granulomas can be found in regional lymph nodes, and also in distant organs throughout the body. One study found that in a cohort of 91 women with systemic complaints and silicone breast implants, 90% had silicone debris in regional lymph nodes on biopsy.14
In summary, the foreign body response to the breast implant occurs through immune cell interactions with the outer shell protein-coated surface, as well as through particulate debris shedding. It is to be determined which of these are more biologically relevant in causing clinical disease or phenomena and should be a focus of future research.
Breast Implant-Related B Cell-Mediated Immune Responses
B cells are largely associated with the adaptive immune response and have the primary function of creating memory antibodies, cytokine secretion, activation of other immune cells, and antigen presentation. Some question as to the importance of B cells in the peri-capsular environment remain. Although they are only a small percentage of the cells present surrounding biomaterials and implants, they have been shown to play some role in fibrosis around foreign bodies as illustrated in B cell knockout (KO) models that resulted in reduced fibrosis.15
Capsular Tissue
Studies on peri-prosthetic breast implant capsules, smooth and textured, have described that CD20+ B cell populations are increased in the area surrounding the capsule. However, they represent the minority of the total cell population in the capsular environment, which is predominantly T cells.16 However, the B cells present in the capsule, form the reactive germinal centers.17 Plasma cells (reactive antibody secreting cells) with polyclonal immunoglobulin light chain production are also found in capsules. These two findings indicate activation of B cell-mediated immunity in the capsular environment. Antibody production may be against local proteins, indicated by high binding of IgG to capsular tissue.18 However, 1 study contradicts these findings. Sanger et al. did not find any increase in deposition of IgG, immunoglobulin M (IgM), or immunoglobulin A in the capsular tissue surrounding long-term breast implants, nor did they find any evidence of humoral activation in the surrounding tissue.19 Notably, B cells were not present in implant exudate 14 days after implant exposure in a rat model.20 However, human analysis of reactive late breast implant seromas (not BIA-ALCL) demonstrates a mixed picture of lymphocytic infiltrate that can vary significantly between patients.21 Other studies on immediate peri-implant response found that when measured at 1-week and 2-week-long exposures to silicone implants, rats had no difference in CD45RA+ B cell levels in exudate compared to controls.20
Our group found that B cell expression markers are elevated in human breast tissue surrounding the capsule compared to the breast tissue of women without implants.11
Serum
This local B cell response may be diluted when analyzed systemically. Serum studies of approximately 300 women from the national Women's Health Study who had breast implants showed no difference in frequency of overall B cell-produced monoclonal antibodies in the peripheral blood.22 Moreover, in 41 women with capsular contracture, no statistical difference was observed in the CD19+ B cells as compared to women without implant contracture.23
However, several studies have identified the differences in silicone-specific antibody production in women with breast implants. Three studies found heightened levels of antisilicone or antipolymer antibodies in women with breast implants, whereas 4 other studies found no difference between women with and without breast implants.18,22,24, 25, 26, 27, 28, 29 One of these studies found that antipolymer antibody levels correlated with the clinical symptoms.29 One rat model identified an early antisilicone lymphocyte response that disappeared after 16 days.30 Probably, the different findings in human antisilicone antibody studies could be attributed to the differences in implant exposure time, implant-specific factors that may elicit an immune response, during which the antibodies were being examined (IgG vs. IgM), or how antibody levels were measured.
Multiple studies have identified the heightened presence of self-antibodies in women with breast implants. These include antithyroglobulin, antimicrosomial, anticollagen, antifibrinogen, and antifibronectin antibodies.31, 32, 33 Other studies have identified the presence of autoantibodies that are more specific to autoimmune disease, such as antinuclear (ANAs), anti-SSA, anti-SSB, anti-Scl70, and anti-dsDNA antibodies.34, 35, 36 One of the largest studies tested 813 women with silicone breast implants and found that 57.8% had positive ANAs, although this study did not have a control group for comparison.34 Notably, another group observed 200 silicone breast implant patients and found no difference in ANAs compared to an implant-naïve control group.37 These differences in study outcomes could be attributable to selection bias for symptomatic patients, implant length of time, or testing method.
Animal models showed similar findings and indicated that silicone acts as an adjuvant. Rats injected with silicone produce higher heterologous antibodies (non-specific to the species, binding to bovine serum albumin and bovine collagen) and higher homologous antibodies (specific to the rat, binding to rat thyroglobulin). Mouse models showed higher serum IgM compared to the control. The antibody response in peripheral blood has been observed to be the most potently activated in response to silicone gel, as compared to silicone oil or liquid.38,39
In in vitro experiments using murine splenic B cells, there was a large increase in antibody-forming B lymphocytes after exposure to mammary implant silicone gel as compared to the control; however, this increase was not statistically significant.40
Overall, there is a mixed picture of the B cell response and its role in modulating immune response after silicone breast implant (Figure 2). The cells appear to be important in the initial fibrosis reaction and long-term antibody response, though less significant than other immune cell populations, such as T cells and macrophages.
Figure 2.
Effect of silicone on B cell immune response. An illustrated example of positive findings in the literature. Findings on the effect of silicone differed in the immediate breast capsule versus that in the serum/blood stream. Notably, 12 of the studies (∼1/3rd) reported negative findings (no B cell activation or response to silicone breast implants).
Limitations
Limitations of this study include the somewhat elusive nature of this topic, potential for bias in study publication, and a paucity of any recent publications. As our primary interest for this topic was to gain a better understanding of the cellular and molecular level interactions between the B cells and silicone breast implants, we purposefully excluded any studies that focused exclusively on clinical symptomatology. Although we could identify several studies with negative findings (no difference in B cell immune responses between women with silicone implants compared to controls), there is certainly a known propensity to not publish studies with negative findings. Thus, the results presented here may be skewed toward positive findings. Lastly, it is notable that besides the author's own work, only one other study has been published on this topic in the last decade. The remaining studies were largely published in the 1990s or early 2000s. It is unclear whether this is due to a lack of interest in the topic or perhaps a general feeling that the topic is not of significance after the Institute of Medicine concluded that silicone breast implants are safe and allowed their return to market in 2006. We feel that the crucial impact of this review is to underscore that contemporary studies are needed to confirm prior findings and help resolve whether silicone breast implants have any impact on systemic B cell-mediated immunity.
Conclusion
Understanding the basic immune cell response to silicone provides the cornerstone of understanding the clinical manifestations of breast implant-associated pathology. Multiple studies point to B cell activation in response to the foreign body breast implant. Shared findings among the various experimental models suggest that silicone breast implants may activate B cells in the implant capsule and may have systemic effects on the production of autoantibodies. They may also play a role in the sensitization of B lymphocytes to silicone. Whether this activation of B cells has far-reaching consequences in affecting an individuals’ predilection for systemic disease and cancer development or prevention is still an ongoing area of research. Further research is needed regarding the impact of breast implants on other arms of the immune system to better understand their long-term biological impact.
Acknowledgements and Conflicts of Interest
Iulianna Taritsa, BA: The author has no significant conflicts of interest with any companies or organization whose products or services may be discussed in this article.
Puja M. Jagasia, BA: The author has no significant conflicts of interest with any companies or organization whose products or services may be discussed in this article.
Michael Boctor, BA: The author has no significant conflicts of interest with any companies or organization whose products or services may be discussed in this article.
John Y. Kim, MD: The author has no significant conflicts of interest with any companies or organization whose products or services may be discussed in this article.
Megan Fracol, MD: The author has no significant conflicts of interest with any companies or organization whose products or services may be discussed in this article.
Contributions of Authors
Iulianna Taritsa, BA: Participated in writing, data analysis, and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted.
Puja M. Jagasia, BA: Participated in writing, data analysis, and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted.
Michael Boctor BA: Participated in writing, data analysis, and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted.
John Y. Kim MD: Participated in research design, writing, data analysis and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted.
Megan Fracol MD: Participated in research design, writing, and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted.
No funding from any source was received for this work.
No generative AI was employed for this work.
Ethical approval: Not required.
Footnotes
Meetings Presented: Midwestern Association of Plastic Surgeons (MAPS) 61st Annual Scientific Meeting, held in July 14-16, 2023 at the Grand Geneva Resort in Lake Geneva, Wisconsin.
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