Plain Talk: Immunology 101

Immunologiaa selkokielellä


Collins Dictionary – Immune response: “The reaction of an organism’s body to foreign materials (antigens), including the production of antibodies”

An immune response is comparable to a well-orchestrated military defence strategy. The first line of defence is the physical barrier – the epithelial cells of the skin, respiratory tract, and digestive system – that act as borders against invading pathogens. When a pathogen breaches this barrier, such as through a splinter that penetrates the skin, local innate immune cells – the border guards – become activated. These immune sentinels, including tissue-resident macrophages and mast cells, are strategically positioned beneath the epithelium and detect danger via so-called pattern recognition receptors or pre-existing antibodies in cases of secondary infections. Once activated, they release inflammatory mediators like TNF-α, IL-1β, and IL-6 (also known as pyrogens), which cause the body’s temperature to rise (fever). Although fever might feel uncomfortable, it’s not something that always needs to be reduced right away. In fact, fever is part of the body’s natural defence mechanism – it helps boost the immune response and makes it harder for bacteria and viruses to grow and spread. The pyrogens also make nearby blood vessels more “leaky” by increasing their permeability, allowing more water and immune cells to pass through the vessel walls into the surrounding tissue. This leads to the typical swelling of a wound and facilitates the easier infiltration of additional immune cells, including monocytes and neutrophils, into the affected tissue.

The recruited monocytes function like police officers, coordinating the response, while neutrophils act as frontline soldiers, arriving in huge numbers within the first hours of infection. This massive infiltration can be in some cases seen as pus formation at the infection site. Circulating factors like complement factors or antibodies (B cells) in the bloodstream also accumulate in the wound, serving as traps that mark, immobilize, and destroy invading pathogens. Monocytes and neutrophils possess specialized receptors that recognize foreign structures conserved on pathogens or bound antibodies, which triggers the uptake and phagocytosis of pathogens. With other words: innate immune cells literally eat up the pathogens. On top of this activity, neutrophils can commit suicide and undergo programmed cell death, which causes the release of their sticky DNA. The process is known as neutrophil extracellular traps (NET) and the DNA entangles pathogens, thereby preventing their spread. The DNA:pathogen complexes are also easier to phagocytose.

Dendritic cells, which are comparable to spies and teachers, also play a role in pathogen phagocytosis, although their direct influence on controlling acute infections is minimal. Instead, their primary function is to eat and digest pathogens that they sample at the infection site (like spies) and then breaking them down into small fragments (peptides or antigens) to display these fragments on major histocompatibility complex (MHC) molecules. At the same time, the dendritic cell becomes activated and migrates to the nearest lymph node, where it searches for a specialized “contract killer” – a T cell trained to recognize the specific pathogen-derived fragment. To initiate this alliance, the T cell’s receptor must precisely match the pathogen-derived peptides displayed on the dendritic cell’s MHC molecules, ensuring a targeted immune response. If a T cell recognizes the specific structure displayed by an activated dendritic cell, it initiates a rapid proliferation process, generating millions of identical copies of itself – the reason why lymph nodes are swelling during infections. This expansion equips the immune system with a vast army of trained killers, ready to mount a targeted defence against any invading pathogen. However, the generation of antigen-specific T cells requires around 10 days after infection and does not contribute to the initial immune defence.

But let’s get back to the place of infection, where the infection can now follow different paths:

I. Resolution by innate immunity : In an optimal scenario, the present innate immune cells such as macrophages and neutrophils successfully eliminate the invading pathogens, primarily through phagocytosis within approximately one week. If all pathogens are cleared rapidly, there is no continued recruitment of further neutrophils. Monocytes already present in the affected tissue are not activated anymore by danger signals and undergo a phenotypic shift from a pro-inflammatory to a pro-resolving state. These reparative monocytes contribute to scar formation, fibrosis, and tissue remodeling, processes that are essential for restoring homeostasis and tissue integrity. Meanwhile, the initiation of an adaptive immune response becomes redundant, but still protects against a second infection.

II. Failure of innate containment and transition to adaptive immunity: If the initial innate immune response is insufficient to eliminate all pathogens (see I), the infection progresses. Persistent presence of pathogens and ongoing tissue damage lead to further recruitment of neutrophils and monocytes, amplifying the inflammatory response. At the meantime, dendritic cells instruct T cells in the nearby lymph node as discussed above. A small number of T cells, whose receptors specifically recognize these foreign antigens, become activated (or “primed”), begin to proliferate rapidly, and thereby create a clonal army of pathogen-specific cells. The activated effector T cells are then recruited to the site of infection. These cells coordinate a more targeted immune attack, including the activation of B cells to produce pathogen-specific antibodies and the instruction of macrophages.

After the infection is cleared, a subset of T and B cells undergoes differentiation into long-lived memory cells. These specialized cells remain in the body for years or even a lifetime, patrolling tissues or waiting in lymphoid organs. If the same pathogen infects us again, these memory T cells start a faster, stronger, and more efficient secondary immune response, often neutralizing the threat before symptoms even develop. (However, it is worth noting that prolonged inflammation carries a risk of collateral tissue damage and, if unresolved, may contribute to chronic inflammation or even autoimmunity, especially if self-antigens are exposed or mimic microbial epitopes.)

III. Failure of containment and transition to sepsis: When innate and adaptive immune defences fail to control the pathogen locally, for instance because the immune system is weakened (as during some cancer treatments) the infection may spread beyond the original site into the circulation. The presence of pathogens in the blood can lead to systemic inflammation and results in sepsis. The universal presences of pathogens and their products are recognized throughout the body by all innate immune cells simultaneously, which triggers widespread activation of immune pathways and the body-wide release of cytokines. This cytokine storm, marked by uncontrolled release of pyrogens such as TNF-α, IL-1β, and IL-6, causes vascular leakage in every organ, impaired oxygen delivery, and organ dysfunction, which are hallmarks of septic shock. Accordingly, a sepsis reaction is very similar to the situation at the infection site. The big difference is only that the release of pyrogens during a wound reaction is local – as supposed to be – while the immune reaction during sepsis is systemic. Clinically, patients may experience hypotension, metabolic acidosis, altered mental status, and finally multiorgan failure.

In summary, sepsis is an acute, life-threatening syndrome that mirrors the fundamental principles of a localized wound response as described above; however, it differs by triggering an activation of innate immune cells across entire organs. This widespread inflammatory reaction, rather than remaining confined to the infection site, leads potentially to tissue damage and multi-organ failure.


Cambridge Dictionary – Vaccination: “The process or an act of giving someone a vaccine (= a substance put into a person’s body to prevent them getting a disease)”

The immune system is able to create a lifelong memory against pathogens like bacteria or viruses. This specific memory is encoded in the DNA of T cells and B cells and called adaptive immunity. The word adaptive emphasizes that the immune response can be trained, adjusted and specified, which is indeed the case. Accordingly, you can take advantage of this fact and target the adaptive immune system against any specific pathogen or any protein of your choice. This is exactly what physicians are exploiting during vaccination: They use the principles of an immune reaction (How does an inflammatory reaction look like?), but train the adaptive immune system against a pathogen of their choice.

The adaptive immune system possesses a remarkable ability: it can distinguish between “self” and “non-self” proteins. This capacity is essential for protecting the body against pathogens while avoiding harm to its own tissues. However, not all foreign proteins initiate an immune response. If the immune system were to react to every foreign molecule, such as dietary proteins or airborne particles, we would live in a constant state of inflammation. Everyday actions like eating or breathing could trigger immune activation that leads to chronic inflammation and illness. This is precisely what occurs during allergic reactions, where the immune system mounts a response against otherwise harmless antigens.

To prevent such detrimental overreactions, the adaptive immune system has evolved mechanisms to respond selectively to proteins that pose a genuine threat, typically those associated with pathogenic organisms. But this raises an important question: how does the immune system recognize which proteins are dangerous and which are harmless?

The key lies in a two-signal requirement for initiating an adaptive immune response. The first step involves dendritic cells, which are a component of the innate immune system. These cells patrol the body, engulf (phagocytose), and process proteins encountered in their environment (How does an inflammatory reaction look like?). On their own, however, these proteins – whether foreign or even self-derived – do not automatically trigger an immune response. If they did, the system would risk attacking the body itself or mounting unnecessary reactions to harmless antigens. Therefore, dendritic cells require a second signal to become fully activated and competent to instruct T cells. This second signal arises from danger signals, e.g. molecular structures unique to microbes, that are sensed by dendritic cells. For example, bacterial cell walls contain lipopolysaccharides, which are absent in human cells. Similarly, although DNA and RNA consist of the same basic building blocks in all life forms, their methylation patterns and structural features differ between host (us) and pathogen, especially in viruses and bacteria. During the course of evolution, the immune system developed receptors that are able to recognize these structures and act as molecular “danger signals,” alerting dendritic cells to the presence of a pathogen.

Once dendritic cells phagocytosed a protein and at the same time get triggered by microbial signatures, they become activated and migrate to the lymph nodes, where they present the processed peptides (antigens) on major histocompatibility complex (MHC) molecules to naïve T cells – now accompanied by the co-stimulatory signals that signify danger. This interaction ensures that the T cell becomes activated only in the presence of genuine danger, allowing the adaptive immune response to be triggered precisely when needed. Therefore, injecting an antigen on its own fails to generate antigen-specific T cells or establish immune memory, as it does not sufficiently activate dendritic cells; in fact, the opposite occurs: the immune system enters a state of tolerance, becomes unresponsive to the antigen, and actively suppresses any reaction to avoid autoimmunity or unnecessary inflammation. This raises an important question: if antigens alone are insufficient to elicit immunity, how do vaccinations – based on the injection of selected antigens – successfully generate protective immune responses and long-lasting memory?

The answer relies in the two-signal system: both components – the antigen and the danger signal that activates dendritic cells – have to be injected to the patient at the same time. This principle underpins the success of vaccination strategies, which cleverly combine antigens with immune-activating cues. A historical example illustrates this beautifully: Edward Jenner, a doctor in Berkeley, had the theory that a person who had contracted cowpox would be immune from smallpox (the cowpox virus is closely related to the Variola virus that causes smallpox, but the disease course of cowpox is much milder and less virulent compared to smallpox). In his first vaccinations – performed in 1796  – he used the pus in blisters from patients suffering of cowpox and exposed a child to it. It turns out that the child developed a mild form of cowpox, but was immune to a later smallpox infection. From 1800 onward, this immunization was called vaccination because it was derived from a virus affecting cows (Latin: vacca ‘cow’). In Jenner’s case, the vaccination was effective because he transferred the pus from an active infection site, which still contained live cowpox viruses. These viral particles could be phagocytosed by dendritic cells, which not only processed the antigens but were also activated through danger signals unique to the virus. This dual two-signal engagement allowed the dendritic cells to initiate a robust immune response and educate T cells accordingly. Due to the structural similarity between the cowpox and smallpox viruses, the immune response triggered by cowpox conferred cross-protection against smallpox.

Similarly, live attenuated vaccines use weakened forms of the actual pathogen that are no longer capable of causing disease in healthy individuals but still maintain their immunogenicity – their ability to trigger an immune response. Because they mimic a natural infection, these vaccines typically elicit a strong, durable immune response, often requiring fewer booster doses. This form is used to immunize against MMR (measles, mumps, rubella), varicella (Chickenpox), rotavirus, BCG (bacillus Calmette–Guérin for tuberculosis), influenza (nasal spray), vaccinia (used for smallpox), dengue (dengvaxia), and others.

Another form of vaccination uses inactivated vaccines. These use pathogens that have been killed or inactivated so they can’t replicate when transferred, but they still carry the necessary danger signals to activate dendritic cells. Inactivated vaccines often require booster doses. Currently, vaccination with inactivated vaccine is used to protect against hepatitis A, influenza (injection), polio (IPV – inactivated polio vaccine), cholera (injected form), tick-borne encephalitis, and others.

Another strategy to induce an immune response against a pathogen involves the direct administration of purified pathogen-derived proteins, also known as subunit vaccines. With advances in biotechnology, it is now possible to generate these proteins in the laboratory and use them as highly targeted vaccine components. By introducing only a specific protein, these vaccines can direct the immune system’s attention to a critical part of the pathogen. However, as discussed earlier, the immune system does not automatically respond to every foreign protein. Many of these isolated proteins do not inherently act as danger signals and therefore fail to activate dendritic cells on their own. Without this activation – i.e., without a second signal – the dendritic cell is not able to instruct T cells and effectively trigger an immune response. To overcome this challenge, so-called adjuvants are often included in protein-based vaccines. These are substances designed to mimic danger signals or induce inflammation, thereby providing the necessary co-stimulatory signals to activate dendritic cells. This approach is widely used in vaccines such as Hepatitis B and HPV, where subunit vaccines paired with potent adjuvants have proven to be both safe and effective.

The newly established mRNA vaccines (like those developed for COVID-19) contain synthetic messenger RNA that encodes a specific protein from the target pathogen – often the surface spike protein in the case of SARS-CoV-2. This mRNA is packaged inside lipid nanoparticles (fat bubbles) to shield the mRNA molecule and facilitate its entry into human cells. Once in the organism, dendritic cells absorb the lipid nanoparticles and the synthetic mRNA is released into the dendritic cells’ cytoplasm and translated into the viral protein. In this case, the lipid nanoparticles and certain modified features of the synthetic mRNA act as danger signals and adjuvant. Subsequently, the dendritic cell gets activated, while the newly made viral protein is displayed on the cell surface via MHC class I molecules necessary to activate cytotoxic T cells.

There is a common concern that mRNA from vaccines could integrate into the human genome. Scientifically, however, this is not feasible – mRNA lacks the necessary properties to incorporate into DNA for several important reasons:

1) mRNA stays in the cytoplasm: It never enters the cell nucleus, where our DNA is stored.

2) mRNA is structurally different from DNA (see RNA and DNA sections above). Only a protein such as the reverse transcriptase is able to revert mRNA to DNA. However, the gene that encodes for this enzyme is exclusively found in some viruses, but does not exist in humans or mRNA vaccines.

3) Even if RNA were somehow turned into DNA, humans would need integrase enzymes to insert the foreign DNA into our genome. Again, only some viruses possess these tools, but eukaryotes like humans don’t.

A viral vector vaccine uses a harmless virus (like an adenovirus) as a delivery system (or vector) to transport genetic instructions into our cells. These instructions encode a protein from the target pathogen (like the SARS-CoV-2 spike protein), which your body will then recognize and develop immunity against. The viral vector itself also serves as a natural adjuvant and cause dendritic cell activation. This built-in immune activation often eliminates the need for additional adjuvants.

Similar to mRNA vaccines, also this system is unable to integrate into the DNA because it lacks integration enzymes. Most viral vectors (like adenovirus-based ones) lack the integrase enzyme, which is needed to integrate viral DNA into host genome. This enzyme is present in retroviruses like HIV, but not in viral vectors used in vaccines. Furthermore, vectors used for vaccination are genetically modified to be replication-deficient and cannot amplify. Examples of viral vector vaccines are the COVID-19 vaccines Johnson & Johnson, Sputnik V, and AstraZeneca, and the Ebola vaccines Ervebo.