The physiological roles of lysosomes are the clearance of defective cellular material through autophagy, the digestion of endocytosed material, as well as the repair of the plasma membrane and the control of energy metabolism [1]. Thus, lysosomes are important for human health and regulation of the physiological aging process and increasing evidence supports that dysfunction of lysosomes is a key factor in many neurodegenerative diseases such as Alzheimer or Parkinson disease [2]. The enzymatic activities of lysosomes require an acidic pH, and they are particularly sensitive to membrane permeabilization and oxidiative stress. Consequently, lysosomes need to be protected by special mechanisms.
Two recent papers address one of these mechanisms, and the first one has encouraged us to write this comment. In this study, protection of lysosomes has been linked to the extracellular lipid binding protein, the lipocalin Apolipoprotein D (ApoD). ApoD is targeted to the lysosomes, where it helps to prevent membrane permeabilization and alkalization upon oxidative stress [3]. Thus the lysosomes remain capable of autophagy upon neurodegeneration. The ApoD mediated preservation and protection of lysosomal function and integrity has further been proposed in the case of the lysosomal storage disease Niemann Pick type A (NPA), where lack of ApoD accelerated the symptoms of the disease in an NPA mouse model [4]. Further, the addition of exogenously added ApoD relieved membrane permeabilization and alkalization of lysosomes in fibroblasts derived from human NPA patients.
This comment aims to point to an additional mechanism by which lysosomes might be protected, by the action of antilysosomal autoantibodies. Such an activity was described more than half a century ago and is no longer present in the discussions.
In contrast to the previously assumed idea of “the horror autotoxicus“ suggested by Paul Ehrlich, by which autoantibodies preferably lead to inflammation and damage of organisms, it is well recognized that natural autoantibodies exist which can also play positive roles [5]. Beneficial autoantibodies against proinflammatory cytokines, or beneficial anti-DNA antibodies may even be used to treat diseases like rheumatoid arthritis or systemic lupus erythematosus (SLE) [6]. Other natural autoantibodies can be involved in tumor surveillance or help to eliminate oxidatively damaged cell components [7]. In this way, natural autoantibodies may also protect against atherosclerosis [8].
The existence of protective antilysosomal autoantibodies, in particular with regard to SLE, but also in patients with hepatitis, has been described more than half a century ago [9][10]. Already in 1964 researchers in the lab of Peter A. Miescher at the New York University described different anti-cytoplasmatic antibodies, most of them IgG, some also IgM [9]. In contrast to the IgG antibodies, these IgM antibodies were not cytolytic, not antitoxic, and acted as stabilizing antibodies for lysosomes. Their possible protective activity was investigated by phagocytosis experiments, showing that lysosomes, that were incubated with these antibodies, were protected from phagoytosis by human leucocytes [10]. These experiments were compatible with the assumption that some autoantibodies, preferentially IgM, may preserve the integrity of lysosomal structures. Thus, when searching for therapeutic interventions against degenerative diseases, where the loss of lysosomal integrity plays an important role, not only the protective factor ApoD, but also protective autoantibodies could be employed. With the help of current techniques such as the generation of human monoclonal antibodies by single cell RT-PCR and recombinant expression [11], such protective molecules could be provided and so justify the renaissance of this interesting research field.

References
1. Xu H & Ren D (2015) Lysosomal physiology Annu. Rev. Physiol. 77:57–80 [https//doi:10.1146/annurev-physiol-021014-071649 PMID: 25668017]
2. Stoka V, Turk V & Turk B (2016) Lysosomal cathepsins and their regulation in aging and neurodegeneration Ageing Res. Rev. 32:22–37 [https://doi:10.1016/j.arr... PMID: 27125852]
3. Pascua-Maestro R, Diez-Hermano S, Lillo C, Ganfornina MD & Sanchez D (2017) Protecting cells by protecting their vulnerable lysosomes: Identification of a new mechanism for preserving lysosomal functional integrity upon oxidative stress PLoS Genet. 13:e1006603 [https://doi:10.1371/journ.... PMID: 28182653]
4. Pascua-Maestro R, Corraliza-Gomez M, Fadrique-Rojo C, Ledesma MD, Schuchman EH, Sanchez D & Ganfornina MD (2020) Apolipoprotein D-mediated preservation of lysosomal function promotes cell survival and delays motor impairment in Niemann-Pick type A disease Neurobiol. Dis. 144:105046 [https://doi:10.1016/j.nbd... PMID: 32798728]
5. Avrameas S (1991) Natural autoantibodies: from 'horror autotoxicus' to 'gnothi seauton' Immunol. Today.12:154–9 [https://doi: 10.1016/S0167-5699(05)80045-3. PMID: 1715166]
6. Shoenfeld Y & Toubi E (2005) Protective autoantibodies: role in homeostasis, clinical importance, and therapeutic potential Arthritis Rheum. 52:2599–606 [https://doi:10.1002/art.2... PMID: 16142758]
7. Lutz HU, Binder CJ & Kaveri S (2009) Naturally occurring auto-antibodies in homeostasis and disease Trends Immunol. 30:43–51 https://doi:10.1016/j.it.... PMID: 19058756]
8. Binder CJ (2010) Natural IgM antibodies against oxidation-specific epitopes. J. Clin. Immunol. 30, Suppl. 1:S56–60 [https://doi: 10.1007/s10875-010-9396-3. PMID: 20387104]
9. Miescher PA, Wiedermann G, Hirschhorn R & Weissmann G (1964). Possible protective activity of antilysosomal autoantibodies in patients with hepatitis. J. Clin. Invest. 43:1266–& (Meeting Abstract) (not in PubMed, only ISI)
10. Wiedermann G & Miescher PA (1965) Cytoplasmic antibodies in patients with systemic lupus erythematosus Ann. N. Y. Acad. Sci. 124:807–15 [https://doi:10.1111/j.174... PMID: 5214840]
11. Tiller T, Meffre E, Yurasov S, Tsuiji M, Nussenzweig MC & Wardemann H (2008) Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning J. Immunol. Methods. 329:112–24 [https://doi: 10.1016/j.jim.2007.09.017 PMID: 17996249]