Innate immunity

What is innate immunity? State two features that distinguish it from specific (or acquired) immunity.

Analyze the following two experimental situations involving mouse models infected by a virulent pathogenic microorganism:

• Mouse A: mutant lacking phagocytes and NK cells (cellular innate immunity absent), but with intact B and T lymphocytes.

• Mouse B: athymic mutant with a block in V(D)J recombination (adaptive immunity absent: no functional lymphocytes), but with intact phagocytes and NK cells.

1. a) Reasonably predict the progression of the bacterial load and the expected outcome in both mice during the first week post-infection.
2. b) Based on the deduced results, refute the following statement with biological arguments: "Since adaptive immunity is much more specific and possesses immunological memory, innate immunity is a rudimentary and dispensable mechanism in higher vertebrates."

Name three external barriers that hinder the entry of pathogens into the body and explain how one of them acts.

The skin and mucous membranes constitute the first line of defence. State two physical or chemical mechanisms by which they hinder infections.

Tears, saliva and sweat contain lysozyme. Explain what lysozyme is and how it contributes to defence against bacterial infections.

Mucus and the cilia of the airways form a defensive barrier. Explain how this cleaning system works and reason why smoking weakens it.

A patient with third-degree thermal burns covering 40 % of their body is admitted in critical condition. A few days later, they develop a severe systemic infection caused by common opportunistic bacteria from the environment.

1. a) Justify why the destruction of the epidermis not only eliminates a mechanical barrier, but also neutralizes two chemical components and one biological component characteristic of cutaneous innate defenses that actively prevent microbial colonization in intact skin.
2. b) In the burned area, there is a massive release of histamine and tumor necrosis factor (TNF-α). Explain the cause-and-effect physiological relationship between these local mediators, hypovolemia (loss of intravascular volume into the interstitium), and the ease with which superficial colonization rapidly progresses to bacteremia or septicemia.

Name two types of leukocytes that act in innate immunity (neutrophils, macrophages, NK cells) and state briefly what each of them does.

What is phagocytosis? Briefly describe its main stages, from the recognition of the pathogen to its digestion inside the phagocyte.

What are NK (natural killer) cells? Explain what type of abnormal cells of the organism itself they destroy and why they are considered part of innate immunity.

Observe the sequence of phagocytosis performed by a macrophage. Describe what occurs in each of the numbered stages (1 to 3) and explain what pus is and how it forms.

Distinguish the characteristic functions of the following leukocytes of innate immunity: neutrophils, monocytes and macrophages, eosinophils, basophils and NK cells.

After a cut in the skin, neutrophils quickly arrive at the area and, later, macrophages. Explain what each cell type does, why they arrive in that order and how the cellular debris is removed once the infection has been controlled.

Cytomegalovirus (CMV) induces the degradation of major histocompatibility complex class I (MHC-I) in the host cell. However, the virus also synthesizes its own viral protein (UL18) that is inserted into the plasma membrane, mimicking the three-dimensional conformation of MHC-I, although it is incapable of presenting peptides.

1. a) Justify the selective advantage that this dual strategy provides to the virus, deducing what cellular fate the infected cell would suffer if the virus merely eliminated MHC-I without expressing the UL18 decoy when interacting with cytotoxic T lymphocytes (CD8+) and natural killer (NK) cells.
2. b) If a CMV strain were engineered with a loss-of-function mutation in the UL18 protein gene, predict which innate immune system population will selectively eliminate these infected cells and through what balance of surface signals its lytic mechanism will be activated.

Explain what the inflammatory response is, what its four characteristic signs are (redness, heat, swelling and pain), and why, despite being uncomfortable, it is a beneficial response.

Fever is an innate immune response. Explain why a moderate rise in body temperature can hinder the multiplication of pathogens and stimulate the body's defences.

Explain what interferons are, which cells produce them and how they hinder the multiplication of viruses in neighbouring cells even though they do not act directly on the virus.

Two patients with primary hereditary immunodeficiencies are analyzed: patient A has a null mutation that completely abolishes the synthesis of complement factor C3, whereas patient B has a deletion that prevents them from synthesizing factor C9 (a component of the membrane attack complex or MAC).

1. a) Reasonably predict which of the two patients will exhibit greater vulnerability to generalized pyogenic bacterial infections, justifying your answer based on the complement pathways and effector functions that are abolished in each case.
2. b) In a laboratory assay, Escherichia coli is incubated with normal human neutrophils and serum from patient B. Will phagocytosis of the bacterium occur? Justify your answer by describing the molecular mechanism involved.

In a laboratory, the phagocytosis of Streptococcus pneumoniae by human macrophages cultured in vitro is being investigated. Two strains are compared: the wild-type S strain (encapsulated) and the mutant R strain (which does not synthesize a capsule), subjected to three prior experimental conditions:

1. Preincubation in sterile culture medium (without serum).

2. Preincubation with fresh serum from a healthy individual never exposed to the pathogen nor vaccinated.

3. Preincubation with fresh serum from an individual who recently recovered from pneumococcal pneumonia.

1. a) Predict and justify under which conditions (1, 2, or 3) massive phagocytosis of the S strain will occur, detailing the complementary molecular role of innate and acquired opsonins.
2. b) The R strain is noticeably phagocytosed even under condition 1, whereas the S strain is not. Justify at the molecular and cell surface level why the polysaccharide capsule prevents direct recognition by phagocyte receptors.

During the genesis of an atheromatous plaque, the deposition of oxidized lipoproteins (oxLDL) in the arterial intima attracts monocytes that differentiate into tissue macrophages. By phagocytosing oxLDL without managing to fully metabolize it, they turn into foam cells.

1. a) Explain how a set of originally adaptive and protective responses of innate immunity (the secretion of proinflammatory cytokines, reactive oxygen species, and matrix metalloproteinases) triggers the long-term destabilization and rupture of the atheromatous plaque.
2. b) A student reasons: "If inflammation is an innate defense designed to repair tissues, inducing low-grade chronic inflammation in blood vessels should keep the immune system alert and protect the arteries." Refute their hypothesis by justifying why chronicity alters the reversibility and resolution of the inflammatory process.

In septic shock caused by Gram-negative bacteria, lipopolysaccharide (LPS) massively activates Toll-like receptors (TLR-4) on intravascular and tissue macrophages, triggering an uncontrolled secretion of TNF-α, interleukin-1 (IL-1), and nitric oxide into the general circulation.

1. a) Analyze the physiological paradox: why do vasodilation and increased endothelial permeability, which are highly effective at eradicating a bacterial infection locally, cause generalized cellular hypoxia, lactic acidosis, and multiple organ failure when they occur systemically?
2. b) In a preclinical trial, an irreversible inhibitor of inducible nitric oxide synthase (iNOS) is administered to animals with sepsis. Predict with reasoning the effect this drug will have on mean arterial pressure, and justify why this intervention alone does not guarantee tissue survival or the recovery of capillary perfusion.

Macrophages, besides phagocytosing, act as antigen-presenting cells. Explain what this function consists of and why it makes macrophages a bridge between innate immunity and specific immunity.

The microbiota of the skin and of the gut hinders colonisation by pathogens. Explain two mechanisms by which it achieves this and reason what can happen to defences after prolonged treatment with broad-spectrum antibiotics.

A patient undergoing chemotherapy presents with fever and an acute bacterial skin infection. The blood test shows 400 neutrophils/µL (severe neutropenia; normal values: 2000-7500/µL), but their levels of tissue macrophages and lymphocytes are normal. Despite having viable macrophages in the dermis, the infection progresses rapidly in the first 24 hours.

1. a) Justify why the exclusive presence of macrophages is not enough to contain the acute bacterial infection without the assistance of neutrophils, taking into account the relative abundance, recruitment kinetics (diapedesis), and microbicidal mechanisms of both cells.
2. b) If a bacterial vaccine against the invading pathogen were administered to this patient at that moment, predict with reasoning the short-term efficacy of such a measure in halting the ongoing infectious process.