The autoimmune process and beta cell destruction

Your immune system recognizes and attacks foreign agents, such as viruses and bacteria, but leaves your own body's cells untouched. This ability to tell apart what is yours from what is foreign is called self-tolerance. An autoimmune disease occurs when this mechanism breaks down, and the immune system mistakenly attacks the body's healthy cells and tissues, producing inflammation and destruction [1].

Autoimmune diseases are common worldwide and include conditions such as rheumatoid arthritis (an attack on the joints), Hashimoto's thyroiditis and Graves' disease (the thyroid), lupus, multiple sclerosis and celiac disease. Type 1 diabetes is an autoimmune disease in which the attack is directed specifically against the beta cells in the pancreas, the cells that produce insulin [1]. If you have type 1 diabetes, you have a somewhat higher risk of developing another autoimmune disease as well, such as chronic thyroiditis or celiac disease, which is why your doctor may recommend check-ups for these conditions [2].

The pancreas contains small groups of hormone-producing cells called the islets of Langerhans, and inside each islet are the beta cells, which produce insulin. In type 1 diabetes, the cells of the immune system enter these islets through a process called insulitis, that is, inflammation of the islets [3]. The immune cells surround the beta cells and destroy them gradually, while the other cell types in the islet remain largely untouched. This selective destruction gradually lowers your ability to produce insulin.

The destruction happens through several pathways at the same time. Cytotoxic T lymphocytes (CD8+) make direct contact with a beta cell and release toxic molecules that force it to die [4]. In parallel, the inflammatory molecules called cytokines, released during insulitis, create a hostile local environment that stresses the beta cells and can affect even those that are not in direct contact with an immune cell. As the destruction advances, insulin production falls, and when a significant part of the beta cells has been lost, blood glucose begins to rise and symptoms appear.

The attack is led by the adaptive immune system. The helper T lymphocytes (CD4+) act as coordinators, directing and amplifying the immune response. The cytotoxic T lymphocytes (CD8+) are the main direct killers of the beta cells [4]. The helper cells of the immune system (dendritic cells and macrophages) take up some proteins from the beta cells and show them to the T lymphocytes (they are thus antigen-presenting cells), activating them. Besides their role as presenters, macrophages also have the role of sustaining the inflammation in the islet. B lymphocytes contribute insignificantly, only by producing autoantibodies, which however do not destroy the beta cell.

A central role is also played by the HLA system (human leukocyte antigens), a universal platform through which protein fragments are presented to the T lymphocytes. Certain variants of the HLA genes present beta cell proteins in a way that triggers autoimmunity more easily [5]. The autoantibodies that the doctor measures are directed against four main targets in the beta cell: insulin (IAA), glutamic acid decarboxylase (GAD65), insulinoma-associated antigen 2 (IA-2) and zinc transporter 8 (ZnT8) [3]. These autoantibodies are very useful markers of the disease, but the actual destruction of the beta cells is carried out by the cytotoxic T lymphocytes (CD8+), not by the autoantibodies.

Type 1 diabetes has a silent, symptom-free (preclinical) phase, which can last from a few months to many years, before symptoms appear. This period is divided into two preclinical stages [6]. Stage 1 means the presence of two or more autoantibodies, with normal blood glucose and no symptoms. Stage 2 means that the autoantibodies persist and blood glucose becomes abnormal (prediabetes), with symptoms still absent. Stage 3 is the clinical onset, with high blood glucose and the classic symptoms, such as excessive thirst, frequent urination, weight loss and fatigue.

The autoimmune process usually begins early in life, and the speed at which it advances varies greatly from one person to another, from a few months to over a decade. An important point is that, starting from stage 1, we are already talking about the presence of the disease, not just a simple risk [6]. This staging underpins screening programs such as TrialNet and T1Detect, which aim to detect the disease before a dangerous emergency (diabetic ketoacidosis) appears.

Type 1 diabetes arises from a combination of a genetic predisposition and certain environmental factors. The strongest genetic contribution comes from the HLA region, where certain combinations of genes considerably increase the risk, while others are protective [5]. However, the genes alone are not enough, because most people who carry the risk genes never develop the disease, and in identical twins, when one has type 1 diabetes, the other develops it in only about half of cases. These facts show that the environment has a decisive role in the onset of the disease.

The main suspects among the environmental factors are viral infections, especially certain viruses that can infect the beta cells [7]. One of the ways a virus can start the attack is molecular mimicry, that is, the resemblance between viral proteins and those of the beta cells [8]. The role of the gut flora (the bacteria in the intestine) and of the diet in the first years of life is also discussed [9]. The exact trigger cannot be identified, and the disease was not caused by anything you or your parents did. It cannot be a matter of anyone's fault, but only of a complex process that research is still studying.

Yes. At the time of diagnosis, the immune attack has already destroyed most of the beta cells, but usually some functional cells remain. The doctor assesses this remaining function by measuring C-peptide, a molecule released in amounts equal to insulin [10]. Precisely because some beta cells survive, shortly after starting insulin treatment many patients go through a temporary phase called the “honeymoon” (partial remission) [11]. During this period, the remaining beta cells recover part of their function, blood glucose becomes easy to control, and the need for external insulin drops a great deal.

This period is temporary, because the autoimmune process has not truly stopped. In the months and years that follow, the immune system continues to destroy the remaining beta cells, C-peptide falls, and in the end the insulin requirement rises again (the remission ends). Preserving even a small beta cell function is valuable, because it is associated with better blood glucose control, fewer dangerous drops, and a lower risk of long-term complications [12]. For this reason, protecting the beta cells is an important goal of current research.

The speed at which the beta cells are lost varies greatly, and the main factor is age. Young children usually have the fastest progression, with more aggressive insulitis and a faster loss of beta cells, while adults often progress much more slowly. The number and type of autoantibodies also matter: more autoantibodies tend to predict a faster progression, while the presence of a single type of autoantibody may indicate a slower progression, perhaps even a reversible one [6].

The genetic background and the moment in life when the autoimmunity began also influence the pace. The clearest example of slow progression is LADA (latent autoimmune diabetes in adults), an autoimmune form with slow progression that appears in adulthood [13]. LADA is often confused at first with type 2 diabetes, but it eventually leads to insulin dependence.

The autoimmune attack is remarkably selective for the beta cells. The other hormone-producing cells in the islets of Langerhans, such as the alpha cells (which produce glucagon) and the delta cells (which produce somatostatin), are not destroyed and survive in an almost normal number [3]. Studies carried out on human pancreas confirm that the beta cells are lost selectively, while the alpha and delta cells survive.

Survival, however, does not mean normal functioning. Although the alpha cells are preserved, their function becomes deregulated, and the release of glucagon is no longer correctly controlled by the blood glucose level [14]. Too much glucagon released at the wrong moment can worsen hyperglycemia, and an insufficient glucagon secretion response during hypoglycemia removes an important safety net and increases the risk of severe hypoglycemia. This deregulation occurs mainly as a result of the loss of the normal signals coming from the neighboring beta cells, not from a direct destruction of the alpha cells by the immune system.

For decades, researchers have been trying to go beyond simply replacing insulin with external injections (or the pump) and to develop a disease-modifying treatment, that is, one that slows or even stops the autoimmune attack. The reference example is teplizumab, an anti-CD3 monoclonal antibody and the main disease-modifying treatment currently approved for type 1 diabetes [15]. It acts by calming the autoreactive T lymphocytes that attack the beta cells and, in people in stage 2, it can delay the moment of onset of clinical disease (stage 3) by about two years.

It is important to understand that this treatment delays the disease but does not stop it and does not cure it, and not all people respond to it. Stronger immunosuppression brings serious risks, such as infections. A curative treatment does not exist yet, because we cannot yet re-educate the immune system to tolerate the beta cells and rebuild the lost beta cell mass. Current research directions include combinations of immunotherapies, approaches that induce tolerance, and the replacement of beta cells with insulin-producing cells obtained from stem cells [16]. Many of these lines of research are in advanced clinical trials.

Islet (or pancreas) transplantation can restore insulin production, but the beta cells transplanted into a person with type 1 diabetes face two distinct immune threats. The first is graft rejection: the recipient's immune system attacks the donor tissue simply because it is genetically foreign. The second threat, specific to the autoimmune disease, is autoimmune recurrence, that is, the reactivation of the initial disease, in which the same immune response directed against one's own beta cells now attacks the new cells precisely because they are beta cells [17].

The main reason the disease recurs is immunological memory. The autoreactive T lymphocytes created during the initial disease persist for years or even decades in a latent state and reactivate when beta cell antigens appear again [17]. The usual anti-rejection treatment is designed mainly to control immunity against the received foreign tissue (alloimmunity) and does not reliably suppress these already trained memory cells. This double threat — alloimmunity and autoimmunity — is the main reason islet transplants fail over time and explains why simply replacing the beta cells is not, in fact, a treatment that definitively cures the disease.