INNATE IMMUNITY: AN EMERGING FOCUS FOR THERAPEUTIC INTERVENTION

Long under appreciated by basic and clinical researchers, molecular and cellular components of innate immunity have now re-emerged as attractive targets for therapeutic intervention in inflammatory and autoimmune diseases. Innate immunity is a central focus of the science and business of Celtaxsys.

Innate Immunity: a first line of defense against invasion and tissue damage

Innate immunity encompasses several protective mechanisms that provide a first line of defense against tissue damage for all multicellular organisms (plants and animals). 
The front line of innate immunity is conferred by properties of the biological barriers, such as skin, airways and intestinal tract, which form our interface with the outside world. This is augmented by the constant presence of antimicrobial molecules (for example, mucus and enzymes) in sweat and other exposed body fluids that can trap, starve or directly kill unwanted microorganisms.
Innate immunity kicks into high gear when faced with acute and/or persistent danger signals, which fall into two main categories:

• Microorganism-Associated Molecular Patterns (MAMPs) from viruses, bacteria, fungi, multicellular parasites, such as DNA, for example.
• Damage-Associated Molecular Patterns (DAMPs), which accumulate upon abnormal death and oxidative stress of host cells:  Advanced Glycation Endproducts (AGEs) are a well-known example of a DAMP.

When MAMPs or DAMPs are present, white blood cells (leukocytes) of the innate immune system respond in force. The recognition of danger signals, MAMPs and DAMPs, occurs by specialized receptors, named pattern-recognition receptors (PRRs), present on innate immune cells. PRRs are present and active at the time of birth (hence the name “innate”). In contrast, receptors of the adaptive immune system arise by mutation and selection in response to life events, such as exposure to a virus (hence the name “adaptive”). In adaptive immunity, each individual features its own unique set of abilities to respond to a specific threat at a given point in time. Innate immunity is shared by all members of a species and is always on.

 

Cells of the Innate Immune System
Innate immune functional responses are orchestrated by specialized subsets of leukocytes. In humans, innate immune leukocyte subsets fall into three main categories: granulocytes, monocytes, and natural killer cells.  Granulocytes are so named because they contain dense bodies, or granules, filled with antimicrobial and pro-inflammatory biochemicals. The granulocyte family consists of specialized cells called neutrophils, eosinophils, basophils, and mast cells. Granulocytes are often the first responders when a danger pattern is sensed.
Innate immune leukocytes mount quick responses (in seconds to minutes) to danger signals emitted in tissues, due to both their residence in the tissues and their ability to very rapidly enter into tissues from blood.
Functional innate immune responses mounted by leukocytes in tissues include:

• Secreting biochemicals that can tag, trap, starve or directly kill unwanted microorganisms
• Disposing of unwanted microorganisms by eating them (a process called phagocytosis)
• Disposing of abnormal or inflected host cells by killing them
• Signaling other immune cells to join the effort
• Stimulating the repair process by signaling tissue cells, such as fibroblasts, to rebuild the protective barrier

In the last decade, compelling evidence has accumulated that innate immune responses not only form a crucial, first line of defense against damage, but also are a necessary and sufficient element for the development adaptive immune responses carried out by the adaptive immune system (T & B cells). For example, PRR-mediated activation of innate immune cells by vaccines is absolutely required for a protective antibody response to arise. Additionally, it is now recognized that all innate immune cell types are able to mediate development of adaptive immunity which, particularly for granulocytes, stands in stark contrast with textbook knowledge.

Innate immunity is linked to inflammatory and autoimmune diseases and cancer
A successful innate immune response is characterized by the removal of the source of the danger signal(s) and is limited in time, space, and resources put into action.  However, genetic predispositions, virulent microorganisms and other factors can derail innate immune responses.  The vicious circle stemming from persistent danger signals and continuous recruitment and activation of innate immune cells in tissues can lead to inflammatory disease.
From a pathological viewpoint, local accumulation of innate immune cells and their by products (notably biochemicals released by neutrophils proteases) can activate adaptive immune response against one’s own innate immune cells, resulting in autoimmune disease. Recent evidence also demonstrates that cancer cells can evolve clever strategies to avoid recognition by PRRs and learn to activate innate immunity to increase nutrient flow and growth. Thus, innate immune mechanisms are also of high clinical relevance in cancer.
A schematic view of innate immunity is presented in the Figure and text below and explained further below.

 

Figure caption:
Schematic view of innate immune responses. Danger signals from microorganisms (microorganism-associated molecular patterns, or MAMPs) and host cells (damage-associated molecular patterns, or DAMPs) are key to initiation of innate immune responses, via the activation of pattern recognition receptors (PRRs), which are shared by all members in a species (“innate” receptors).  Innate immune leukocytes are then activated and mount a functional response.  The ideal outcome (labeled as “pass”, in green) will remove the initial danger signal and be limited in time, space and resources, leading to a resolution of the innate immune response.  However, a vicious circle may ensue, with further emission of danger signals, sensing by PRRs and activation of innate immune leukocytes (labeled as “fail”, in red), leading to chronic inflammatory or autoimmune disease.

 

References
DAMPs, PAMPs and alarmins: all we need to know about danger. Bianchi ME. J Leukoc Biol. 2007; 81(1):1-5. Review. PMID: 17032697
The inflammasomes: molecular effectors of host resistance against bacterial, viral, parasitic, and fungal infections. Skeldon A, Saleh M. Front Microbiol. 2011; 2:15. Review. PMID: 21716947