- Do physiologically normal adults have autoantibodies? A categorical yes with the caveat that human antibody repertoire is most frequently probed by examining antibodies present in serum derived from circulating blood. The caveat being presence in serum does not and cannot extrapolate to the rest of the body.
- Non-specialists frequently overlook/misinterpret/conflate two issues about autoantibodies
- One, autoantibody ≠ autoimmunity.
- Two, circulating autoantibody ≠ autoantibody in target tissue.
- Natural antibodies are those detected in circulation in absence of known/overt immunizations.
- So-called natural antibodies circulating in our body include those that bind to antigenic epitopes expressed by our own body (1; see figure below), i.e. autoantibodies.
- Antigens that bind to natural antibodies include constitutively expressed as well as altered glycosylation (addition of variety of sugar molecules) or oxidation (chemical reaction yielding oxide versions of molecules) products.
- How much of natural antibody is autoantibody? Estimates suggest ~20%.
- A likely underestimate since normal serum components such as proteins, glycoproteins, glycolipids and phospholipids are already bound to autoantibodies, masking their antigen-binding sites and rendering them undetected unless specific methods are used to dissociate the antibody from its naturally bound antigen, something rarely done.
- Most autoantibodies are IgM, i.e. germ-line and not class-switched to IgG (1, 2; see figure below).
- As such, they are of low affinity, i.e. bind weakly to their antigenic targets.
- They are also highly cross-reactive, i.e. bind to epitopes (antigen bits) that different antigens have in common.
- They can also be polyreactive, i.e. bind to structurally different molecules apparently lacking common epitopes.
Possible function of autoantibodies
- In 1965, Pierre Grabar proposed that natural autoantibodies may be involved in normal tissue homeostasis by actively clearing out the tissue and cell debris that’s part and parcel of normal physiology (3, 4, 5).
- Theoretical models about the inflection point(s) that convert(s) autoantibody (largely benign) to autoimmunity (disease state) have largely ignored Grabar’s idea that autoantibodies could be involved in maintaining normal physiology.
- In most autoimmune diseases, tissue and cell debris accumulates suggesting impaired/malfunctioning/overwhelmed/inadequate tissue and cell debris clearance processes.
- Two implications about autoimmunity ensue from this observation,
- One, it likely entails impaired ability to manage normal tissue wear and tear.
- Two, such impaired clearance ability in turn likely results in abnormal inflammation.
- Clearance of tissue and cell debris as part and parcel of normal physiology may well be a key fundamental attribute of natural autoantibodies.
- Irun Cohen‘s ‘Immunological homunculus‘ hypothesis (6) proffers a somewhat overlapping explanation for the presence of autoantibodies in healthy people. However, its purview remains within the domain of immunosurveillance, i.e. looking out for and eliminating pathogenic moieties, whether they ensue from the body’s own cells or from without, and not normal physiological tissue homeostatic processes, a fine but critical distinction.
- As Stratis Avrameas puts it, rather than embody Paul Ehrlich‘s ‘horror autotoxicus‘, natural autoantibodies represent ‘gnothi seauton‘ or know thyself, i.e. learning and dealing safely with the inevitable breakdown products of normal physiology (1).
- Hewing to this logic, natural autoantibody repertoire and specificity are remarkably stable within and between species (1, 7, 8, 9).
- That fine but critical distinction? I surmise it renders obsolete the original definition of immunosurveillance, to survey and clear ‘altered’ self. When altered self is inevitable in normal physiology, immune function entails lifelong learning about all sorts of physiological alterations (growth, puberty, pregnancy, aging as examples), and dealing appropriately with them. Appropriately here means without overt inflammation or with limited, self-contained inflammation that doesn’t alter/impede normal tissue and bodily function. In this conceptual framework, autoantibodies are not just normal but also necessary, and their health versus disease difference entails not presence versus absence but rather context and outcome. Likely also differences in titers, specificities and isotypes.
- Any explicit evidence that autoantibodies are part of normal physiology? Closest is their abundant presence in newborns (9, 10, 11, 12, 13), and even human cord blood (14, 15).
Natural anti-cancer antibodies
Are they present in healthy people? Are patterns (specificities and titers) of autoantibodies similar between autoimmune diseases and cancer? Are they present in circulation or in specific tissues or both or either? Could their presence be indicative/diagnostic of cancer? Depending on the answers, at least two implications ensue,
- One, mechanistic, as in possible common pathways for autoimmunity and cancer, even if immunological outcomes are completely opposite as in excessive versus insufficient.
- Two, practical, as in specific circulating autoantibody signatures could be used for cancer diagnosis, especially early diagnosis and/or for prognosis, and certain anti-tumor antibody clones could even be useful in cancer therapy.
Do healthy people have anti-tumor antibodies? Yes (16; see figure below).
- When screened against cultured RT4 bladder carcinoma cells, sera from a few out of 144 healthy volunteers had antibodies that could specifically bind bladder carcinoma antigens (17).
- When screened against cultured astrocytoma cells, sera from a few out of 200 healthy male volunteers aged 18 to 60 years of age had antibodies that could specifically bind astrocytoma antigens (18).
- The Thomson-Friedenreich antigen (T-Ag) is a carbohydrate antigen expressed on normal cell membranes but at much higher levels on certain malignant cells (19).
- Sera from healthy people had natural anti-T-ag antibodies (20).
- Anti-T-ag antibody titers were higher in healthy versus ovarian or endometrial cancer patients (21).
- Tumor-binding monoclonal antibodies derived from natural antibodies predominantly utilize the lambda-light chain (>90%) compared to only ~40% lambda-light chain usage by the normal unstimulated B cell repertoire (22;see figure below), suggesting they arise from specific and not random/stochastic processes.
- Majority of natural anti-tumor cytotoxic antibodies found so far are IgM and they bind to carbohydrate epitopes (16).
- Healthy humans have circulating IgM antibodies that bind to a neuroblastoma-specific cell-surface protein (23, 24).
- These natural IgM antibodies are cytotoxic in vitro to neuroblastoma cells (25).
Some examples of natural anti-tumor antibodies and their effector functions
- SAM-6 is a human mAb (monoclonal antibody) derived from an antibody originally isolated from a gastric cancer patient (26).
- SAM-6 appears to only bind malignant tissue (27), specifically to a tumor-specific isoform of GRP78, the epitope of an O-linked carbohydrate (28).
- When SAM-6 binds to cancer cells in vitro, they die following accumulation of intracellular lipids (26).
- PAM-1 is a human germline-encoded IgM mAb (29).
- It binds to a 130kDa membrane glycoprotein expressed by ~ all epithelial cancers of every type and origin but not on healthy tissues (31, 31).
- PAM-1 binding to cells induces apoptosis both in vitro and in vivo (32).
In the final analysis, it’s safe to conclude that
- Autoantibodies are part of normal physiology, and include anti-tumor specificities.
- Autoantibody repertoire of health, autoimmunity and cancer overlap (33, 34; see figure below, also compare autoantibody targets listed in this figure with those in the 1st figure for obvious overlaps such as DNA, collagen, phospholipids).
- Context, outcome, titers, specificities and isotypes are some of the obviously likely key differences between these physiological states.
- Avrameas, Stratis. “Natural autoantibodies: from ‘horror autotoxicus’ to ‘gnothi seauton’.” Immunology today 12.5 (1991): 154-159.
- Mouthon, Luc, Sébastien Lacroix-Desmazes, and Michel D. Kazatchkine. “Analysis of self-reactive antibody repertoires in normal pregnancy.” Journal of autoimmunity 11.3 (1998): 279-286.
- Grabar, P. “Some considerations of the problem of auto-antibody formation.” Texas reports on biology and medicine 23 (1965): Suppl-1.
- Grabar, Pierre. “” SELF” AND” NOT-SELF” IN IMMUNOLOGY.” The Lancet 303.7870 (1974): 1320-1322.
- Grabar, Pierre. “Autoantibodies and the physiological role of immunoglobulins.” Immunology Today 4.12 (1983): 337-340.
- Cohen, Irun R. “The cognitive paradigm and the immunological homunculus.” Immunology today 13.12 (1992): 490-494.
- Vollmers, H. Peter, and Stephanie Brändlein. “Natural antibodies and cancer.” Journal of autoimmunity 29.4 (2007): 295-302.
- Nobrega, Alberto, et al. “Global analysis of antibody repertoires. II. Evidence for specificity, self‐selection and the immunological “homunculus” of antibodies in normal serum.” European journal of immunology 23.11 (1993): 2851-2859.
- Mouthon, Luc, et al. “Invariance and restriction toward a limited set of self-antigens characterize neonatal IgM antibody repertoires and prevail in autoreactive repertoires of healthy adults.” Proceedings of the National Academy of Sciences 92.9 (1995): 3839-3843.
- Mouthon, L., et al. “The Self‐Reactive Antibody Repertoire of Normal Human Serum IgM is Acquired in Early Childhood and Remains Conserved Throughout Life.” Scandinavian Journal of Immunology 44.3 (1996): 243-251.
- Merbl, Yifat, et al. “Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics.” Journal of Clinical Investigation 117.3 (2007): 712..
- Madi, Asaf, et al. “The natural autoantibody repertoire in newborns and adults.” Naturally Occurring Antibodies (NAbs). Springer New York, 2012. 198-212.
- Wang, Chunguang, et al. “Natural antibodies of newborns recognize oxidative stress-related malondialdehyde acetaldehyde adducts on apoptotic cells and atherosclerotic plaques.” International immunology (2013): dxt022.
- Chou, Meng-Yun, et al. “Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans.” The Journal of clinical investigation 119.5 (2009): 1335.
- Madi, Asaf, et al. “Tumor-Associated and Disease-Associated Autoantibody Repertoires in Healthy Colostrum and Maternal and Newborn Cord Sera.” The Journal of Immunology 194.11 (2015): 5272-5281.
- Schwartz-Albiez, Reinhard, et al. “Cytotoxic natural antibodies against human tumours: an option for anti-cancer immunotherapy?.” Autoimmunity reviews 7.6 (2008): 491-495.
- Grossman, H. Barton. “Natural antibody to a human bladder carcinoma cell line.” Cancer Immunology, Immunotherapy 13.2 (1982): 89-92.
- Pfreundschuh, M., et al. “Natural antibodies to cell‐surface antigens of human astrocytoma.” International Journal of Cancer 29.5 (1982): 517-521.
- Cerenkov, Oleg, Kersti Lamas, and Milady Miljukhina. “The lower level of natural anti‐thomsen‐friedenreich antigen (TFA) agglutinins in sera of patients with gastric cancer related to ABO (H) blood‐group phenotype.” International journal of cancer 60.6 (1995): 781-785.
- MacLean, G. D., and B. M. Longenecker. “Clinical significance of the Thomsen-Friedenreich antigen.” Seminars in cancer biology. Vol. 2. No. 6. 1991.
- Kusama, M. et al. “Natural antibody against Thomsen-Friedenreich antigen in sera of patients with carcinomas and infectious diseases.” The Journal of Nihon University School of Dentistry 35.4 (1993): 241-243.
- Vollmers, H. P., and S. Brändlein. “Natural IgM antibodies: from parias to parvenus.” (2006).
- Ollert, Markus W., et al. “Normal human serum contains a natural IgM antibody cytotoxic for human neuroblastoma cells.” Proceedings of the National Academy of Sciences 93.9 (1996): 4498-4503.
- Ollert, M. W., et al. “Mechanisms of in vivo antineuroblastoma activity of human natural IgM.” European Journal of Cancer 33.12 (1997): 1942-1948.
- David, Kerstin, et al. “Human natural immunoglobulin M antibodies induce apoptosis of human neuroblastoma cells by binding to a Mr 260,000 antigen.” Cancer research 59.15 (1999): 3768-3775.
- Pohle, Tina, et al. “Lipoptosis tumor-specific cell death by antibody-induced intracellular lipid accumulation.” Cancer research 64.11 (2004): 3900-3906.
- Brändlein, Stephanie, et al. “The human IgM antibody SAM-6 induces tumor-specific apoptosis with oxidized low-density lipoprotein.” Molecular cancer therapeutics 6.1 (2007): 326-333.
- Rauschert, Nicole, et al. “A new tumor-specific variant of GRP78 as target for antibody-based therapy.” Laboratory Investigation 88.4 (2008): 375-386.
- Brändlein, Stephanie, et al. “Natural IgM antibodies and immunosurveillance mechanisms against epithelial cancer cells in humans.” Cancer research 63.22 (2003): 7995-8005.
- Hensel, Frank, et al. “A novel proliferation-associated variant of CFR-1 defined by a human monoclonal antibody.” Laboratory investigation 81.8 (2001): 1097-1108.
- Brändlein, Stephanie, et al. “Cysteine-rich fibroblast growth factor receptor 1, a new marker for precancerous epithelial lesions defined by the human monoclonal antibody PAM-1.” Cancer research 63.9 (2003): 2052-2061.
- Brändlein, Stephanie, et al. “PAM-1, a natural human IgM antibody as new tool for detection of breast and prostate precursors.” Human antibodies 13.4 (2003): 97-104.
- Lleo, Ana, et al. “Definition of human autoimmunity—autoantibodies versus autoimmune disease.” Autoimmunity reviews 9.5 (2010): A259-A266.
- Bei, R., et al. “A common repertoire of autoantibodies is shared by cancer and autoimmune disease patients: inflammation in their induction and impact on tumor growth.” Cancer letters 281.1 (2009): 8-23.