Introduction to Immunology: The Innate Immune System

Image Source: Cell Signaling Technology, illustrating innate immunity cell types.

COVID-19, Measles, Salmonella, Monkeypox—all diseases that the immune system is built to fight. Everyday, your immune system stands guard ready to attack anything harmful that enters your body, whether it’s bacteria, viruses, infections, or parasites. This complex defense system works tirelessly—day and night—to detect and destroy these harmful invaders, keeping you alive and healthy. Without it, even minor infections could become life-threatening. By protecting us from countless pathogens throughout our lives, the immune system is essential to our survival. 

All the cells of the immune system originate from hematopoietic stem cells located in the bone marrow. These cells then give rise to two main progenitors: the lymphoid and myeloid—each of which differentiate into a variety of cell types. Thus, the immune system can be categorized into two major branches: the innate immune system of the myeloid lineage and the adaptive immune system of the lymphoid progenitors. Now, let’s shrink down to the cellular level and see the innate immune defense system in action. 

The small, microscopic pathogen encounters the first line of defense: physical and chemical barriers. 

• Skin: your skin, or epidermis, is the body’s most outer layer of defense—almost like a shield; however, even a cut or little abrasion of the skin can cause pathogens to enter. 

• Mucous Membranes: Found in the respiratory, gastrointestinal, and urinary tracts, these membranes trap the pathogens in mucus, For example, when inhaling air, you also breathe in harmful substances that the mucosa in your nose and lungs can catch, preventing them from reaching your internal organs. 

• Chemical Barriers: There are several chemical barriers that act as an additional defense mechanism. In the stomach, hydrochloric acid (HCL) can kill pathogens that make it past the mucous membrane. Lysozyme—found in sweat, saliva, and tears—breaks down the cell walls of certain bacteria. 

But what if the pathogen breaches these physical barriers? The initial innate immune system immediately responds. Acting within minutes or hours, it's nonspecific and present from birth, allowing it to respond to a broad range of pathogens without needing prior exposure. Some of the cells of the innate immune system are derived from monocytes, a type of white blood cell in blood and tissues. They differentiate into macrophages or dendritic cells, depending on the signals they encounter. Both of these cells are crucial to the innate system. 

1. Macrophages: These specialized white blood cells are the first responders. Recognizing pathogens by specific characteristics—pathogen associated molecular patterns (PAMPs)—that differ from your own body’s cells, the macrophage engulfs it in a process known as phagocytosis. A vesicle that contains the engulfed material is formed, which then fuses with a lysosome, an organelle containing digestive enzymes that break down the pathogen into harmless waste products. 

2. Dendritic Cells: These cells serve as messengers. After picking up antigens from the pathogen, dendritic cells travel to the lymphatic system where they present these antigens to T cells and B cells of the adaptive immune system, preparing for a more targeted defense which will be touched upon at a later date. 

If the invading pathogens are harmless enough that the macrophages can deal with them alone, then the system goes no further; however, if the attacking army is overwhelming, the macrophages call for assistance, releasing cytokines—signaling proteins that alert the surrounding immune cells and initiate an inflammatory response. Cells recruited include more macrophages, neutrophils, and other phagocytes which destroy the invading pathogens. Additionally, the inflammatory response involves a number of other responses that help contain and fight the infection: vasodilation (widening of the blood vessels), increased vascular permeability, mast cell degranulation (releasing more cytokines that further stimulate the inflammatory response), and activation of the clotting system and kinin system. 

Furthermore, the inflammation itself stimulates the recruited cells to secrete even more cytokines, notably chemicals called interleukins and TNF-α. This is known as the acute phase response which is a more systemic inflammatory response. 

• Interleukin 1: Sent to the brain to produce a fever—high temperatures intolerable to many pathogens—decreased appetite, and lethargy to conserve more energy so the person can fight the infection 

• Interleukin 6: Sent to the liver to produce acute phase proteins that fight infection, repair tissue, regulate inflammation, and transport nutrients. 

• Interleukin 8: Recruits and activates more neutrophils. 

• Interleukin 2 and 12: Activates Natural Killer cells 

• Tumor Necrosis Factor-Alpha (TNF-α): Released and does all of the above by itself 

The complement system is also activated. The complement proteins work together in a cascade to enhance phagocytosis, recruit more immune cells, and directly destroy pathogens through the formation of the membrane attack complex (MAC).There are three main pathways: 

• Classical pathway: Activated by antibody-antigen complexes (requires antibodies).

• Alternative pathway: Activated by microbial products or damaged cells (independent of antibodies).

• Lectin pathway: Activated by lectins (proteins that bind to carbohydrates) that recognize specific molecules on the surface of pathogens.

The innate immune system provides a rapid, nonspecific defense against pathogens through physical barriers, immune cells like macrophages and dendritic cells, and inflammation. While it’s essential for immediate protection, the adaptive immune system takes over to provide a more targeted response. Next, we’ll explore how the adaptive immune system builds on this initial defense.