Study shows autoantibodies behind lifelong risk of viral infection

A new study, published in the Journal of Experimental Medicine, shows that about 2% of the population develop autoantibodies* against type 1 interferons, mostly later in life. This makes individuals more susceptible to viral diseases like COVID-19. The study  is based on an analysis of a large collection of historical blood samples.

Virus infections trigger the cells of the immune system to release type 1 interferons. These proteins act as early messengers that warn uninfected cells and tissues that a virus is spreading. This allows cells to prepare themselves so that they are ready to fight the virus when it reaches them.

In individuals with a compromised type 1 interferon system, severe viral infections can occur because the body cannot mount a full defense. Recent research has shown that about 5 to 15% of people who are in hospital with severe COVID-19 or influenza have a deficiency in their type 1 interferon response. This is because their blood contains autoantibodies—antibodies that target a person's own structures—that bind type 1 interferons and stop the messenger from functioning.

analyzed the blood samples for the presence of autoantibodies against type 1 interferons to find out who had developed the autoantibodies, when this occurred, and how long these autoantibodies lasted in the blood.

The analysis revealed that around 2% of individuals produced autoantibodies against type 1 interferons in their lifetime and that this typically occurred between the ages of 60 to 65. This confirms prior studies that reported that the prevalence of autoantibodies against type 1 interferons might increase with age.

Next, by studying clinical data, researchers were also able to understand which factors contributed to the development of autoantibodies against type 1 interferons. The individuals who developed them appeared to be prone to also producing antibodies against other proteins formed by their own bodies. This so-called loss of self-tolerance can occur in some people as they age.

These individuals may produce antibodies against their own type 1 interferons because they are both prone to making autoantibodies and are exposed to high levels of type 1 interferons, for example, because their immune system produces interferons against other infections at the time. 

Lifelong consequences of autoantibodies: Importantly, the study found that once developed, these autoantibodies remained detectable in the blood of individuals for the rest of their lives. People with autoantibodies against type 1 interferons, even when they had developed them as far back as in 2008, were more likely to suffer from severe COVID-19 in 2020.

These autoantibodies have consequences for individuals decades later, leading to a compromised type 1 interferon system and reduced immunity against viruses.

Understanding these risk factors might lead to future diagnostic tests that can identify older individuals who are more prone to developing this deficiency, and therefore help with measures to prevent autoantibodies ever developing. Identifying individuals with autoantibodies against type 1 interferons could also help to prioritize these people for vaccines or antivirals to prevent severe viral infections.

Sonja Fernbach et al, Loss of Tolerance Precedes Triggering and Lifelong Persistence of Pathogenic Type I Interferon Autoantibodies, Journal of Experimental Medicine (2024). DOI: 10.1084/jem.20240365

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* Antibodies that specifically react with self-antigens are called autoantibodies. These antibodies are generated as a result of the loss of tolerance response against self-antigens and can be pathogenic.

The loss of the ability of the immune system to distinguish between self and nonself antigens is the underlying cause of autoantibody development. Self-antigens against which autoantibodies are generated mainly include proteins, carbohydrates, fats, or nucleic acids. These antigens can be highly tissue-specific or can be found in all cell types.

In clinical setups, serum autoantibody level has become a potent diagnostic biomarker for autoimmune diseases. Besides autoimmune diseases, autoantibodies can be detected in the serum sample of people suffering from cancer or having severe tissue damage.

The most common methods that are used to detect autoantibody levels include indirect immunofluorescence assay, radioimmunoassay, enzyme-linked immunosorbent assay, chemiluminescence immunoassay, and immunoblotting.  

Autoantibodies can also be found in healthy people where they are developed independently of the immune system’s fortification against antigens. For this reason, these antibodies are called natural autoantibodies, which possess a wide range of reactivity against both foreign invaders (microorganisms) and self-antigens.

In a very small fraction of healthy people, these natural autoantibodies eventually trigger the development of autoimmune diseases, such as rheumatoid arthritis.  

How they a re generated? 

Autoantibodies are generated as a result of disrupted central and peripheral tolerance systems, which eventually lead to maturation and differentiation of autoantibody-generating B lymphocytes into autoantibody-releasing plasma cells.

B lymphocytes that produce high-affinity autoantibodies to self-antigen are either eliminated or functionally inactivated, whereas B lymphocytes that produce low-affinity autoantibodies escape the selection process and continue the maturation process.

Natural autoantibodies are primarily generated from (CD5⁺) B-1 lymphocytes, which are the most abundant B cells in the neonatal repertoire, and non-circulating mature B lymphocytes (marginal zone B lymphocytes). B-1 lymphocytes with an effective antigen-presenting ability can play a crucial role in generating pathogenic autoantibodies in various autoinflammatory diseases.

Natural autoantibodies are primarily polyreactive IgM with low-to-moderate affinity against a variety of unrelated antigens. Because of the wide range of reactivity against microbial antigens, natural autoantibodies provide the first line of defense against infection. Moreover, they prevent inflammation by removing oxidized proteins and lipids and dead cells.

By binding self-antigens non-specifically and with low affinity, natural autoantibodies can prevent highly autoreactive clones from reacting strongly with self-antigen. This way natural autoantibodies can maintain immune system homeostasis.

Recombined V(D)J DNA sequences with no or minimal mutation encode natural autoantibodies. Because of their ability to react with self-antigens, natural autoantibodies can initiate autoimmune responses and provide ‘templates’ for the development of high affinity, pathogenic autoantibodies through somatic hyper-mutation and class-switch DNA recombination.

How pathogenic autoantibodies trigger autoimmune diseases?

About 2.5% of autoimmune diseases are caused by autoantibodies. Pathogenic autoantibodies utilize various specific and distinct mechanisms to trigger the disease pathogenesis.

Autoantibody-mediated receptor stimulation

In Graves’ disease, autoantibodies developed against the thyroid-stimulating hormone (TSH) receptor mimic the function of TSH and stimulate the production of thyroid hormones (T3 and T4), leading to hyperthyroidism. In atrophic goiter, instead of stimulating the TSH receptor, autoantibodies can prevent the binding of TSH to its receptor through competitive inhibition, leading to hypothyroidism.

In systemic sclerosis, autoantibodies generated against angiotensin II type 1 receptor and endothelin-1 type A receptor increase the receptor sensitivity to their respective ligands, leading to increased activation of signaling molecules (ERK1/2, PKC-alpha, AP1, and NFkB) and subsequent induction of systemic sclerosis-related pulmonary and vascular pathologies.

Autoantibody-mediated impaired neural transmission

In Myasthenia Gravis, autoantibodies generated against the acetylcholine receptor on the postsynaptic muscle membrane causes component cascade activation and membrane attack complex formation, leading to damage to the postsynaptic membrane.

In anti-N-methyl D-aspartate (NMDA) receptor encephalitis, expression of NMDA receptors in ovarian teratoma along with other signaling cascade leads to the formation of autoantibodies against the receptor through antigen-specific B and T lymphocytes. However, these autoantibodies cannot reach the central nervous system because of the presence of the blood-brain barrier.

Instead, other secondary stimuli, such as systemic infection, ultimately induce the transition of B and T lymphocytes in the brain. As a result, autoantibody concentration increases significantly in the brain, leading to disruption of neuronal compensation mechanism, loss of surface NMDA receptor, and subsequent development of neurological symptoms.

Autoantibody-induced cell death

In autoimmune hemolytic anemia, the destruction of red blood cells or platelets by autoantibodies causes the development of anemia or platelet deficiency, respectively.

Autoantibody-mediated inflammation

In Pemphigoid diseases, autoantibodies generated against the dermal-epidermal junction proteins cause separation of the dermis and epidermis and release of pro-inflammatory mediators. These mediators through a series of signaling cascades induce the generation of reactive oxygen species, which subsequently causes blister formation and skin inflammation.

In rheumatoid arthritis, autoantibodies are deposited in the joints, which in turn activates tissue-resident macrophages and mast cells, leading to the secretion of inflammatory cytokines and chemokines. These pro-inflammatory mediators further induce the recruitment of neutrophils and monocytes from the circulation, leading to excessive joint inflammation.