Why the autoimmune attack returns after the honeymoon

Immune memory is your immune system's ability to react faster and more strongly when it encounters again a target it has already seen. After the first encounter with an antigen (a fragment the immune system regards as irritating), some of the activated cells turn into long-lived memory cells that remain in the body and wait for a possible new encounter [1].

This is the very mechanism by which vaccines give you protection: after exposure to the harmless antigen in the vaccine, immune memory forms, and on a later exposure the memory cells multiply rapidly and stop the infection. In autoimmune diseases, however, this same memory becomes a problem, because it perpetuates a mistaken reaction directed against your own cells — in type 1 diabetes, against the beta cells of the pancreas [1].

During the initial attack, your immune system created memory cells specific to certain beta cell proteins, including insulin. Once formed, these cells retain the target's “address” and keep it for years, ready to react again [2].

In addition, when a beta cell is destroyed, numerous protein fragments are released, and the immune system thus learns to recognise an ever larger number of targets inside it. This phenomenon is called target (epitope) spreading. In this way the memory against the beta cells not only persists but also expands over time, which is why the presence of several types of autoantibodies indicates a broader attack and a higher risk of progression [2].

During the honeymoon, two opposing processes act in parallel. On one hand, the improvement is based on the resumption of insulin secretion by the remaining beta cells, which recover fairly well but whose number is limited. On the other hand, the autoimmune attack sustained by the memory cells has not stopped and continues to destroy these cells [3].

When the beta cell reserve drops below a certain threshold, your own insulin production becomes insufficient, blood glucose rises and the need for insulin from outside returns. This is why the honeymoon is, by its very nature, temporary — a window of temporary improvement that closes as the beta cells are once again attacked by the immune system [3].

Yes. A characteristic feature of type 1 diabetes is the presence of autoreactive memory T lymphocytes, belonging both to the helper category (CD4+) and to the killer category (CD8+). They specifically recognise proteins from the beta cell [4].

In healthy people, the lymphocytes that, despite all precautions, could recognise the beta cells usually remain inactive throughout life. In people with type 1 diabetes, these same lymphocytes bear the signs of repeated exposure to the target, and some of them become memory cells. These long-lived cells are the long-term engine of the disease [4].

Because memory T cells are especially resistant. They are long-lived and self-renew for years, they are activated more easily than ordinary cells, they depend less on the presence of several activation signals, and they are more resistant to the medicines that suppress the immune system [4].

In addition, autoimmunity arises precisely when the mechanisms that keep in check the lymphocytes wrongly directed against one's own body fail, on a background of genetic predisposition (especially the HLA system) [5]. Once this barrier has been crossed and the memory has formed, simply reducing inflammation temporarily does not rewrite the faulty immune programme, and the population of autoreactive cells can rebuild at any time after a possible immunosuppressive treatment.

Because a person with type 1 diabetes already has an immune memory prepared against the beta cells. When your body receives new islets, two attacks appear at the same time: the resumption of the autoimmune disease (the memory lymphocytes immediately recognise insulin and the other proteins) and the classic rejection of a transplant coming from another person [6].

The two simultaneous attacks rapidly destroy the graft in the absence of medicines that suppress the immune system, which is why an islet transplant from a donor compulsorily requires continuous immunosuppression. Unlike a transplanted kidney, which is not attacked by autoimmunity, the islets remain vulnerable to the return of autoimmunity even under immunosuppressive treatment [6].

This is one of the great hopes of research, but for now it remains largely experimental. Ideally, only the cells wrongly directed against the beta cell would be eliminated, leaving untouched the rest of the immune system, which protects you from infections [7].

Several directions are being explored, from therapies that target the markers of memory cells to approaches that try to “re-educate” the autoreactive lymphocytes [8]. The major challenges are achieving real selectivity only against the autoimmune lymphocytes (without weakening the general defence), the durability of the effect, and the fact that we do not know precisely all the targets under attack, especially after the attack has spread [7].

Exhaustion is a state in which lymphocytes exposed for a long time to the same target gradually lose their ability to attack: they multiply more weakly, kill less efficiently and display on their surface numerous “braking” receptors. The phenomenon was first described in chronic infections and in cancer [9].

Exhaustion is, in fact, a mechanism by which the body limits the destruction caused by its own lymphocytes. In type 1 diabetes this phenomenon could be beneficial: if the autoreactive lymphocytes become exhausted, they attack the beta cells less. Indeed, people with slow disease progression and exhaustion of the autoreactive CD8 lymphocytes preserve their beta cell function for longer, which is why some lines of research are testing immunotherapies that try to push these lymphocytes towards a state of exhaustion [9].

Yes. Immune memory is not equally durable for all targets. For some infections or vaccines protection lasts a lifetime, whereas for others it declines visibly over time, especially in older people [10].

Immune memory is maintained through a population of cells in constant renewal, and when the target is absent or decreases, some of the memory cells may decline in number or lose their strength. Reducing the demand on the beta cells could slow the maintenance of the faulty autoimmune memory. Nevertheless, as long as the beta cells exist and are required to secrete insulin, the target remains present and feeds this memory [10].

Conceptually, yes — this is the rationale of transplanting one's own stem cells. The principle is for an intense suppression of the immune system to erase a large part of the cells wrongly directed against the body, after which the stem cells rebuild a new, more tolerant immune system. In patients with newly diagnosed type 1 diabetes, this procedure has allowed periods of insulin independence, but some of them relapsed and resumed treatment [11].

In some autoimmune diseases, immune resetting can produce prolonged remissions, by restoring the regulatory lymphocytes and “rewriting” the immune response [12]. In type 1 diabetes, however, resetting with one's own cells has not given the same results: as a rule the procedure does not cure definitively, and the disease returns. The reasons are that some autoreactive cells survive the procedure, the genetic predisposition is not corrected, and insulin and the beta cells remain present and can wrongly re-stimulate the rebuilt immune system [5].

Because it depends on the individual balance between the secretory function of the beta cells preserved at the moment of diagnosis and the aggressiveness of the autoimmune attack. The honeymoon tends to be longer in those diagnosed at an older age (after puberty), in those who did not have ketoacidosis at onset, and in those with a larger beta cell reserve [13].

Good blood glucose control, established early, reduces the stress on the beta cells and helps preserve them. In short, the more beta cells are saved and the less extensive the attack, the longer the period of remission tends to be. Be careful, however: not even the longest remission means a cure.