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."

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.

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.

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.

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.

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.

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 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.