autoimmune research, Uncategorized

The Future of the Autoimmunity Continuum

Written by: Bonnie Feldman, DDS, MBA, Ellen M. Martin, Hailey Motooka, Sarah Hinton

The words: Crohn’s, Lupus, and Celiac, contain meanings that differ for everyone, depending on our preconceptions or lack thereof. To some people, these are unfamiliar words that could pass as Pokemon names or Scrabble plays. To others, they are medical jargon used in commercials about unfamiliar medications with millions of different side effects. One way or another, most of us have no understanding of what Crohn’s, Lupus, and Celiac are, even if you append the word disease to them. In fact, 90% of Americans cannot name a single autoimmune disease despite that 16% of the US population is affected by one or more autoimmune diseasesmore people than cancer and cardiovascular disease combined.

incidence & prevalence

Why are people so incognizant of these diseases and their large and growing prevalence?

Maybe we just know so little about what autoimmune diseases really are. For decades, practitioners and researchers classified autoimmune diseases as they did cardiovascular or pulmonary diseases, focusing on specific locations in the body. The most widely accepted definition of autoimmune diseases is the immune system confusing normal cells with foreign or diseased ones or infectious agents and thus mistakenly attacking its own healthy cells and tissues. With continuous improvements in medical technologies, including data analytics, we are gaining a better understanding of the mechanisms that underlie autoimmunity. As a result, our understanding of autoimmune disease has evolved, along with our language to describe related, sometimes newer concepts.

Over the course of our research within the vast literature of autoimmunity, we have discovered discrepancies in how certain diseases are defined. After digging deeper, we found ourselves immersed in a sea of papers containing new classifications and vocabulary. Initially, the learning curve was steep, but over time, we were able to detangle some key terms and definitions that we feel are helpful not only for researchers striving to find answers, but also for patients trying to grasp a better understanding of their own disease, as well as the medical practitioners that diagnose and treat them.

Immune-Mediated Inflammatory Disease: A New Umbrella Term

Definition: Immune-mediated inflammatory disease (IMID) is “a concept used to collectively describe a group of ostensibly unrelated conditions that share common inflammatory pathways.”

This proposed nomenclature is used to describe a spectrum of inflammatory diseases. This continuum of conditions can be classified as autoimmune, autoinflammatory or an overlapping combination. Patients suffering from such IMIDs are predisposed by their genetic heritage. IMID is an umbrella term because it encompasses two branching subcategories: autoinflammatory and autoimmune. These subcategories aren’t restrictive, however, many of the more familiar (i.e. Celiac, Crohn’s, Lupus, RA) autoimmune diseases fall within these classifications along the spectrum.

Innate and Adaptive Immune Systems

First, some essential background on the normal functioning of your body’s immune systems, both Innate and Adaptive (or acquired).

innate and adaptive immunity2
Creative Diagnostics

Innate immunity is the body’s first line of defense against foreign pathogens. Think of them as the bouncers of a club, screening people before they enter, or removing them when they misbehave. However, instead of large muscles and brute strength, their defense tactics consist of cellular and biochemical mechanisms that are poised to respond rapidly to infections. Our innate immune systems are inherited from our evolutionary ancestors going back at least half a billion years. We share many of these mechanisms with distant forms of life like jellyfish, molluscs and worms. Some mechanisms of innate immunity have evolved to deal with molecules common to groups of related microbes (e.g., lipopolysaccharides (LPS) of gram-negative bacteria detected by Toll-like receptors) and do not distinguish finer differences between microbes. Other mechanisms are even more general, serving to prevent any pathogen from entering the body.

The principal components of innate immunity are:

  1. Physical and chemical barriers, such as skin, epithelial membranes and antimicrobial chemicals produced at epithelial surfaces. These barriers don’t need to distinguish friend from foe, but like a castle’s moat or walls, keep random organisms or chemicals out of the body altogether.
  2. Phagocytic cells (neutrophils, macrophages), dendritic cells, natural killer (NK) cells and other innate lymphoid cells. These indiscriminately sequester and consume pathogens or other foreign cells, and send chemical signals to the innate and adaptive systems.
  3. Blood proteins, including members of the complement system and other mediators of inflammation. These chemicals produce a cascade of effects, including local inflammation (e.g., redness and swelling at an infection site), general fever, and additional signalling to the rest of the immune system.

While many different types of cells are involved in the innate immune response, perhaps the most familiar are the macrophages. These large, mobile white blood cells cruise the vascular and lymphatic vessels to locate foreign bodies and essentially, eat them, a process called phagocytosis. Upon detection of foreign viral or bacterial components, macrophages secrete signalling molecules called cytokines. These little chemical messengers carry signals to other cells in the body, activating the adaptive immune system.

Adaptive Immunity, also known as the “acquired immune system,” is comprised of highly specialized white blood cells called B and T cells. These cells are produced as generalized stem cells in the bone marrow and trained to differentiate into cells that attack specific pathogens or infected cells. B cells produce antibodies as their primary chemical weapons and T cells produce cytokines that orchestrate a process of detection and destruction of infected cells.

One aspect of adaptive immunity that differentiates it from innate immunity is its ability to finely detect specific molecules. This is known as specificity, and each population of immune cells specializes in a single signalling molecule or marker. Another unique aspect is the ability to respond more intensely to repeated exposures to the same variety of pathogen. This is known as memory. You are probably familiar with this concept from childhood diseases (which confer immunity to repeated infection) and vaccinations, which “train” the acquired system to recognize pathogens through controlled exposure to live, killed or key molecular fragments of target pathogens.

There are two types of adaptive immune responses:

  1. Humoral Immunity – mediated by antibodies produced by B-cells
  2. Cell-mediated Immunity – mediated by T-cells and their cytokines

Throughout an individual’s lifetime, the adaptive immune system learns which pathogens to attack. Once exposed to a pathogen, such as the flu virus, the adaptive immune system can later identify the same pathogen if exposed a second time. When encountered again, memory B-cells quickly produce antibodies that circulate and attack these specific pathogens.

Autoimmunity vs. Autoinflammatory

Autoimmune Inflammatory: Malfunction in the Innate Immune System

Definition: Autoinflammatory diseases (AIDs) refer to a group of rare and hereditary diseases characterized by recurrent inflammation in the absence of infection, without the unusual presence of antibodies or antigen-specific T-cells typical of autoimmune diseases.

To simplify, in autoinflammatory diseases, the innate immune system reacts without known cause and with ineffective control. As a primary level response, the innate reaction uses white blood cells and acute inflammation to attack unknown “invaders” but is over-reactive, ill-defined, and poorly regulated, that is, the system does not return to calm normalcy once the trigger is removed.

Some examples of autoinflammatory diseases are:

  • Familial Mediterranean Fever (FMF)
  • Neonatal Onset Multisystem Inflammatory Disease (NOMID)
  • Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)
  • Deficiency of the Interleukin-1 Receptor Antagonist (DIRA)
  • Behçet’s Disease
  • Chronic Atypical Neutrophilic Dermatosis With Lipodystrophy and Elevated Temperature (CANDLE)

Autoimmune Disease: Malfunction in the Adaptive (Acquired) Immune System

Definition: Autoimmune disease refers to dysfunctions of the acquired immune system’s defense mechanisms.

Our adaptive immune systems, which we share with all vertebrates (the adaptive immune system started in bony fish hundreds of millions of years ago and has evolved further in our mammalian line of ancestors), control the body’s response to attacks by pathogens by learning to recognize the molecular signatures of these invaders, so that specialized immune cells (B and T cells) can respond more quickly to repeated exposures. In autoimmune diseases, something goes wrong with this process and the immune cells mistakenly learn to target the body’s own healthy tissues, triggering a cascade response that damages tissues and cells.  

The initial inflammation occurs mostly at the locations that the autoantibodies are targeting, but the inflammatory response can progress to other parts of the body.

Some examples of autoimmune diseases are:

Based upon the definitions of autoimmune diseases and autoinflammatory diseases, the distinguishing factor between the two lies in the difference between the specificity or lack of specificity in the immune system’s response— either an innate or adaptive response.

The Disease Continuum

Journal of Pathology

Due to the differences between the innate and adaptive immune systems, diseases are now being classified based on innate/adaptive immunity responses. Boundaries of the continuum have been set with defining factors of both polar ends, but disease classification of this immunological complexity are mostly arbitrary and are not exclusive due to ambiguous overlap in terms of clinical, biological, pathological or genetic features, as shown in the illustration..

The importance of the continuum is to help researchers, practitioners, drug developers and patients recognize that there are many diseases that cannot be classified as solely autoinflammatory or autoimmune. While it is true that inflammation is a symptom of all IMID diseases, regardless of where they fall on the spectrum, distinguishing diseases based on specific immunological response may help to aid in developing, as well as appropriately matching to each patient, more precisely targeted and personalized disease therapies in years to come.

At Your Autoimmunity Connection we are dedicated to adapting to the ever-changing science and understanding of immune mediated diseases. Stay tuned as we continue to update the incidence and prevalence of chronic diseases. While you wait, and while we dive into the research, explore our resources below:

Patient Guide e-book

Movement Therapy e-book

Food Therapy e-book




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  11. Brodin, Petter, et al. “Variation in the Human Immune System Is Largely Driven by Non-Heritable Influences.” Cell, vol. 160, no. 1-1, 15 Jan. 2015, pp. 37–47., doi:10.1016/j.cell.2014.12.020.

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