Lactose metabolism in E. coli is facilitated by two essential proteins, β-galactosidase and galactoside permease. The genes encoding these proteins, along with another enzyme, are organized into a cluster and transcribed together from a single promoter, producing a polycistronic mRNA. These functionally related genes are therefore regulated collectively.
The lac operon is controlled through both positive and negative regulatory mechanisms. Negative regulation occurs as follows: the operon remains inactive when the repressor binds to the operator, blocking RNA polymerase from attaching to the promoter and transcribing the three lac genes. When glucose is depleted and lactose becomes available, the few existing molecules of lac operon enzymes convert lactose into allolactose, which functions as an inducer. Allolactose binds to the repressor, inducing a conformational change that prompts its dissociation from the operator. Once the repressor is removed, RNA polymerase can proceed to transcribe the three lac genes. Genetic and biochemical studies have identified the two primary components of negative control in the lac operon: the operator and the repressor. Additionally, DNA sequencing has revealed two auxiliary lac operators, one upstream and one downstream of the main operator, all three of which are necessary for optimal repression.
Positive regulation of the lac operon, as well as other inducible operons encoding sugar-metabolizing enzymes, is mediated by the catabolite activator protein (CAP) in conjunction with cyclic AMP (cAMP). The CAP-cAMP complex enhances transcription. However, glucose suppresses cAMP levels, thereby inhibiting positive regulation. As a result, the lac operon becomes active only when glucose levels are low, necessitating the metabolism of an alternative energy source. The CAP-cAMP complex facilitates this activation.
The catalytic agent in the transcription process is RNA polymerase. In E. coli, this enzyme consists of a core, which houses the fundamental transcription machinery, and a sigma factor (σ-factor), which guides the core to transcribe specific genes. The σ-factor facilitates the initiation of transcription by enabling the RNA polymerase holoenzyme to bind tightly to a promoter. This σ-dependent binding necessitates the localized melting of 10–17 base pairs of DNA near the transcription start site, forming an open promoter complex. By directing the holoenzyme to bind exclusively to certain promoters, the σ-factor determines which genes will be transcribed. Transcription initiation proceeds until 9 or 10 nucleotides are incorporated into the RNA, at which point the core transitions to an elongation-specific conformation, departs from the promoter, and continues with elongation. The σ-factor is generally released from the core polymerase, though not always immediately after promoter clearance, often exiting stochastically during elongation. The σ-factor can be reused by other core polymerases. Rifampicin sensitivity or resistance is governed by the core, not the σ-factor.
E. coli RNA polymerase achieves abortive transcription through a mechanism called scrunching, in which downstream DNA is drawn into the polymerase without the polymerase physically moving, while retaining its grip on the promoter DNA. The scrunched DNA may store sufficient energy to enable the polymerase to dissociate from the promoter and initiate productive transcription. Prokaryotic promoters contain two key regions located approximately 10 and 35 base pairs upstream of the transcription start site. In E. coli, these regions have consensus sequences of TATAAT and TTGACA, respectively. Generally, the closer a promoter's sequences match these consensus sequences, the stronger the promoter will be. Some exceptionally strong promoters also feature an additional element, known as an UP element, upstream of the core promoter.
Methods for purifying proteins and nucleic acids are fundamental in molecular biology. DNA, RNA, and proteins of varying sizes can be effectively separated using gel electrophoresis. Agarose is the most commonly used gel for nucleic acid electrophoresis, while polyacrylamide is typically employed for protein electrophoresis. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) separates polypeptides based on their sizes. For higher resolution, two-dimensional gel electrophoresis is utilized, combining isoelectric focusing in the first dimension with SDS-PAGE in the second. Ion-exchange chromatography is another technique that separates substances, including proteins, according to their charges, often employing positively charged resins like DEAE-Sephadex.
Labeled DNA or RNA probes can be hybridized to DNAs with identical or very similar sequences on a Southern blot. Modern DNA typing employs Southern blots and multiple DNA probes to detect variable sites in individual organisms, including humans. Additionally, labeled probes may be hybridized to entire chromosomes to identify specific genes or DNA sequences, a process known as in situ hybridization, or fluorescence in situ hybridization (FISH) when fluorescently labeled probes are used. Proteins in complex mixtures can be detected and quantified using immunoblots, or Western blots, where proteins are electrophoresed, transferred to a membrane, and probed with specific antibodies detected via labeled secondary antibodies or protein A.
The Sanger DNA sequencing method relies on dideoxy nucleotides to terminate DNA synthesis, producing DNA fragments of varying sizes that can be analyzed by electrophoresis. The last base of each fragment is determined by the specific dideoxy nucleotide used to terminate the reaction, enabling fragments to be ordered by size, with each one being a single, known base longer than the previous.
To clone a gene, it must be inserted into a vector capable of carrying the gene into a host cell and ensuring its replication. This insertion is typically achieved by cutting both the vector and the target DNA with the same restriction endonucleases to create matching “sticky ends.” Cloning vectors in bacteria are primarily categorized as plasmids or phages.
Plasmid cloning vectors include pBR322 and the pUC plasmids. The pUC plasmids and pBS phagemids facilitate convenient screening, as they possess an ampicillin resistance gene and a multiple cloning site that disrupts a partial β-galactosidase gene. The resulting clones are resistant to ampicillin and lack active β-galactosidase, which is easily identifiable through a color test.
Two prominent types of phage vectors are widely used in cloning. The first is λ (lambda), which has had nonessential genes removed to accommodate inserts, allowing for the insertion of up to 20 kb. Cosmids, combining features of phage and plasmid vectors, can accept inserts up to 50 kb, making them ideal for constructing genomic libraries. The second major type is M13 phages, which offer a multiple cloning region and the ability to produce single-stranded recombinant DNA. This single-stranded DNA is particularly useful for sequencing and site-directed mutagenesis. Phagemids, plasmids with an origin of replication for single-stranded DNA phages, can also generate single-stranded copies of themselves.
Expression vectors are specifically designed to maximize the production of a protein encoded by a cloned gene. Bacterial expression vectors optimize expression by incorporating strong bacterial promoters and ribosome-binding sites, which are typically absent in cloned eukaryotic genes. Most cloning vectors are inducible to control protein production efficiently.
The three primary functions of genes are storing information, replication, and the accumulation of mutations. Proteins, also known as polypeptides, are polymers of amino acids linked by peptide bonds. Most genes carry the instructions for producing a single polypeptide and are expressed through a two-step process: transcription, which synthesizes an mRNA copy of the gene, followed by translation, where this mRNA is used to produce a protein. Translation occurs on ribosomes, the cell’s protein factories, and requires transfer RNAs (tRNAs), which act as adapters capable of recognizing both the genetic code in mRNA and the corresponding amino acids.
Translation elongation involves three key steps: (1) the transfer of an aminoacyl-tRNA to the A site, (2) the formation of a peptide bond between the amino acid at the P site and the aminoacyl-tRNA at the A site, and (3) the translocation of mRNA by one codon length through the ribosome, positioning the newly formed peptidyl-tRNA at the P site. Translation concludes at a stop codon (UAG, UAA, or UGA). A segment of RNA or DNA that includes a translation initiation codon, a coding region, and a termination codon is referred to as an open reading frame. The section of mRNA between its 5'-end and the initiation codon is called the leader or 5'-UTR, while the part between the 3'-end (or poly(A) tail) and the termination codon is referred to as the trailer or 3'-UTR.
DNA replicates through a semiconservative mechanism: as the parental strands separate, each serves as a template for the synthesis of a new complementary strand. A mutation in a gene often leads to a change in the corresponding position within the polypeptide product. Sickle cell disease serves as an example of the harmful effects such mutations can cause.
Cancer is characterized as a malignant tumor, defined by its ability to grow progressively, invade surrounding healthy tissues, and spread to distant sites through a process known as metastasis. These malignant cells are essentially altered versions of the body’s own cells, having escaped normal growth-regulating mechanisms and apoptotic signals, which leads to unchecked proliferation.
From an immunological standpoint, the immune system plays a vital role in cancer surveillance as part of its regular maintenance functions. However, cancer cells often develop mechanisms to escape immune detection. The interaction between cancer and the immune system is explained by a dynamic process called immunoediting, which occurs in three phases:
Elimination: The immune system detects and eradicates newly formed cancer cells.
Equilibrium: A state is reached where there is a balance between the immune-mediated destruction of neoplastic cells and the survival of a small population of cancer cells.
Escape: The most aggressive and least immunogenic tumor cells proliferate and spread, often aided by immune pathways, after developing sophisticated strategies to bypass the immune response.
Cancer cells express various tumor antigens that can be recognized by the immune system, which are categorized as follows:
Tumor-specific antigens (TSAs): Unique proteins arising from DNA mutations or viral infections, resulting in novel, non-self peptides.
Tumor-associated antigens (TAAs): Normal cellular proteins with abnormal expression patterns, such as embryonic proteins expressed in adults (oncofetal antigens) or overexpressed self-proteins.
To evade immune responses, transformed cells utilize several strategies, including downregulation of MHC class I expression, resistance to apoptotic signals, and impaired or blocked costimulatory signals necessary for T-cell activation. These factors can contribute to the establishment of an immunosuppressive microenvironment around the tumor. Additionally, chronic inflammation can paradoxically foster a pro-tumor microenvironment by promoting mutation accumulation and enhancing tumor progression.
Immunodeficiency diseases underscore the critical role of the immune system's cells and molecules in maintaining overall protection against disease. Primary immunodeficiency diseases, stemming from over 300 distinct inherited genetic defects, encompass a spectrum from severe SCID conditions affecting T cells and B cells to milder defects impacting the production of specific immunoglobulin classes or complement components. The most severe SCID cases obstruct the development of all hematopoietic lineages, T and B cells, or T cells alone, which in turn impairs antibody production due to the essential roles of helper T cells in many antibody responses. Advances in early screening now enable the detection of most SCID forms at birth, allowing for infection prevention and timely initiation of therapies. Some of these defects can now be corrected through bone marrow or HSC transplantation, with gene therapy emerging as a promising avenue.
Other primary immunodeficiencies that affect narrower aspects of the immune system, such as antibodies or complement components, may be more readily managed by replacing the missing immune protein through intravenous administration of immunoglobulins or complement components. However, reduced B or T cell counts can result in immune dysregulation, explaining the paradox of immunodeficiency coinciding with autoimmunity. More clearly defined are the mechanisms behind severe autoimmune conditions like APECED and IPEX, which arise from defects in self-tolerance within the thymus or in the generation of regulatory T cells.
Secondary, or acquired, immunodeficiencies occur due to factors that negatively affect immune responses over the course of life, such as malnutrition, immunosuppressive drug treatments, or HIV infection. Various aspects of HIV epidemiology and biology have contributed to its significant global impact. For instance, HIV can be transmitted...
Infectious agents are incredibly diverse and resilient. These predominantly free-living organisms possess several advantages over their human hosts, including significantly more evolutionary time, shorter generational cycles, and extraordinary adaptability. As their hosts, humans also have notable strengths, such as a highly advanced system—comprising both innate and adaptive components—that has evolved through interactions with these infectious agents, both beneficial and harmful. Additionally, humans arguably hold intellectual and technological superiority, which we have effectively employed to combat these threats. From primitive yet effective measures to modern advancements like antibiotics and vaccines, we have achieved remarkable in saving lives, particularly those of young children. Nevertheless, the emergence and re-emergence of infectious diseases are likely to remain persistent challenges. Some of issues can be mitigated through reduced encroachment on animal habitats, efforts to counteract global warming, and improved sanitation practices. Moreover, the recent spread of Ebola to other continents serves as a stark warning: addressing the needs of those most affected by poverty and growing global inequities is a shared responsibility, one that no physical barrier can resolve.
Significant progress has been made in understanding the principles of immune tolerance over the past decade. Previously, tolerance was primarily perceived as the complete elimination of autoreactive cells, adhering to the “ignorance is bliss” model. However, current insights reveal a more intricate understanding of tolerance. Scientists now recognize that while certain structures remain hidden from the immune system’s surveillance (evasion), and the most aggressive anti-self lymphocytes are eliminated (elimination), specific self-recognizing regulatory lymphocytes play a critical role in suppressing anti-self immune responses (engagement). The absence of this regulatory component disrupts the delicate equilibrium. Both central and peripheral tolerance mechanisms have been elucidated through animal models and are now being utilized to manipulate immune tolerance in humans. Various immunotherapeutic approaches are employed to treat autoimmune diseases and prevent immune rejection of allografts, showcasing some of the most promising applications of immune tolerance principles from research to clinical practice.
Immune responses are often a double-edged sword. Their essential role in protecting against infections is critical for survival, as shown by the fatal consequences of untreated immunodeficiency diseases (to be discussed in Chapter 18). To ensure effective protection, a broad range of innate and adaptive immune mechanisms has evolved, typically enabling responses tailored to the specific pathogen entering the body. However, immune responses are inherently destructive, and when excessive, persistent, or misdirected, they can harm the body. This chapter has focused on such conditions, including the four classes of hypersensitivity reactions and chronic inflammation.
Type I hypersensitivity reactions, commonly known as allergies, are mediated by IgE antibodies bound to FcεRI receptors on mast cells, basophils, and eosinophils, which become cross-linked by recognized antigens. This triggers degranulation, releasing mediators responsible for allergy symptoms. These symptoms may manifest locally, such as in the respiratory tract for airborne allergens or in the gastrointestinal tract for food allergens, but they can also be systemic if the allergen enters the bloodstream, as with insect stings, drugs like penicillin, and certain foods. Although IgE and granulocyte degranulation likely evolved to combat parasitic worms and animal or insect venoms, some allergic reactions, such as hay fever, are mostly inconveniences, while others, like anaphylaxis and asthma, are maladaptive and potentially life-threatening.
Type II and Type III hypersensitivity reactions involve normal IgM and IgG antibody-antigen interactions that become harmful when excessive or misdirected. Type II reactions arise from extensive cell destruction, as seen in transfusion reactions involving incompatible blood types.
We conclude our extensive exploration of the cellular and molecular biology of the immune response by emphasizing studies that unveil the dynamic choreography of immune cells within living tissues. These images and videos have not only validated predictions made by immunologists who previously lacked the tools to visualize the cells they studied but have also uncovered unexpected characteristics of immune cells: the striking swarming behavior of neutrophils, the intricate dendritic processes of germinal center B cells, the coordinated interactions of B- T-cell pairs at the follicular boundary, and the distinctive appearance and activity of resident memory T cells in barrier tissues, to name just a few. The chapter concludes with an introduction to studies examining immune cell behavior in pathological conditions, which will serve as the foundation for the next series of chapters focusing on the dual role of immune cells in both combating and contributing to disease.
The barrier immune systems, comprising tissues and cells in the intestinal, respiratory, reproductive, and urinary tracts (mucosal-associated lymphoid tissue or MALT), as well as in the skin, play a crucial role in monitoring and protecting areas of the body exposed to the external environment. Epithelial cells form the first line of innate immunity, with each barrier tissue covered by one or more epithelial layers that collaborate other innate and adaptive immune cells. This coordination fosters a harmonious relationship with the diverse community of microorganisms inhabiting our bodies. The interaction between the microbiome and the immune system strengthens the integrity of epithelial barriers and creates optimal conditions for defending against harmful pathogens. While each barrier tissue has unique characteristics, they share common strategies to promote tolerance to commensal microorganisms through the maintenance of regulatory T cells and IgA-producing B-cell activity, alongside mechanisms that initiate type 1 and type 2 inflammatory responses against organisms that harm barrier tissues. Achieving the delicate balance between tolerance and an inflammatory response to microbes remains a core challenge, addressed through various molecular and cellular immune strategies that are only beginning to be understood.
The adaptive immune system is renowned for its vast diversity of antibody and T-cell receptor specificities. The mechanisms generating this diversity—V(D)J recombination and somatic hypermutation—are unique and highly regarded by scientists in various biological fields. However, another crucial aspect of diversity often overlooked by those outside immunology is the extensive range of immune effector mechanisms, both antibody- and cell-mediated, that provide protection. For humoral responses, this diversity in the biological properties of antibodies—including structural variations, mechanisms for pathogen elimination, ability to traverse tissue layers into different body fluids, resistance to degradation, and longevity in circulation—stems from sequence variation in the constant regions of heavy chain classes and subclasses. These differences evolved in vertebrates due to the adaptive advantage of producing antibodies capable of neutralizing pathogens and targeting infected or tumor cells through multiple mechanisms. These mechanisms include neutralizing and agglutinating antigens, enhancing phagocytosis via opsonization, activating complement pathways leading to cell lysis, inducing antibody-dependent cell-mediated cytotoxicity, and triggering degranulation and mediator release. To enable the generation of antibodies with such diverse functions, the immune system developed a third unique gene-altering process known as heavy-chain class switch recombination (CSR). CSR allows naïve B cells with IgM and IgD B-cell receptors to produce antibody-secreting plasma cells capable of generating antibodies of other classes better suited to combat an invading pathogen. As previously discussed, the regulation of the heavy chain ultimately expressed in an activated B cell reflects this remarkable adaptability.
B cells are defined by the presence of a membrane-bound immunoglobulin receptor, which binds antigens. Upon antigen binding and receiving auxiliary signals, B cells are directed to secrete soluble antibody molecules. There are four main subsets of B cells—B-1a, B-1b, B-2 (follicular), and marginal zone (MZ) B cells—distinguished by their anatomical locations, the antigens they recognize, and their dependence on T-cell help. B-1 B cells predominantly protect body cavities, especially the peritoneal cavity. They can produce antibodies upon antigen stimulation without requiring T-cell help, though T-cell-derived signals can enhance their responses. B-1 B cells are self-renewing in the periphery and primarily secrete IgM antibodies, many of which target carbohydrate antigens. B-1a and B-1b cells are differentiated by the expression of CD5 molecules on B-1a cells. Marginal zone B cells reside in the spleen's marginal zones and are particularly adept at responding to TI-2 antigens. The strategic positioning of B-1 and MZ B-cell subpopulations at antigen entry sites, along with their oligoclonality and cross-reactivity to various microbes, situates them at the interface of innate and adaptive immunity.
B-2 (follicular) B cells are the most prevalent B-cell subset and require assistance from CD4 T cells to respond to antigens. Early in an immune response, B-2 B cells can differentiate into IgM-secreting plasma cells and IgM-bearing memory cells. They also undergo class switch recombination, a process that depends on CD4 T-cell help. Some B-2 B cells migrate into follicles and develop into germinal center B cells, where they collaborate with T cells to undergo somatic hypermutation and antigen-driven selection. These processes result in the production of high-affinity antibodies.
The initial critical challenge in B-cell development is the creation of B cells with an extensive repertoire—billions of B-cell receptor specificities—capable of responding to virtually any foreign element entering the body. The diversity of antibodies, arising from gene rearrangements, junctional diversification, and various combinations of heavy and light chains, is further enhanced by the daily production of millions of new B cells. Unnecessary B cells are replaced by new ones generated in the bone marrow through hematopoiesis and B-cell development processes. Progression through hematopoietic stages, commitment to the lymphoid lineage, and early B-cell development in the bone marrow, leading to the formation of immature B cells, is regulated by transcription factor networks. Of particular significance is the E2A → EBF1 → PAX5 transcription factor cascade, a feed-forward regulatory mechanism where PAX5 activates the genes defining the B lymphocyte phenotype, which remains unchanged until antigen and other signals prompt differentiation into antibody-secreting plasma cells. This intricate transcription factor network is influenced by, and influences, numerous epigenetic modifications controlling the gene transcription and protein expression unique to each stage. The precise and successful recombination of heavy and light-chain genes is integral to, and sometimes drives, the progression through B-cell developmental stages, with checkpoints ensuring proper rearrangements that yield functional BCRs. Following V-DJ recombination, the µ heavy chain undergoes testing to confirm its ability to pair and associate with the surrogate light-chain polypeptide; if successful, the resulting pre-BCR provides the necessary signals for further development.
The fate of a mature, naïve T cell depends on the signals it encounters. Most naïve T cells perish within days or weeks after exiting the thymus, as they fail to bind to MHC-peptide complexes while scanning the surface of antigen-presenting cells (APCs) during their circulation through lymphoid tissues. To survive and differentiate into effector cells, T cells require two signals from activated dendritic cells: one through the T-cell receptor (TCR) and another via a costimulatory receptor, such as CD28.
The effector fate of an activated T cell is further influenced by a third category of signals—polarizing cytokines produced by APCs. These cytokines trigger the expression of master transcriptional regulators that direct the T cell to specific functions, including the secretion of effector cytokines. CD4 T cells, for instance, differentiate into various helper T-cell subsets such as Th1, Th2, Th9, Th17, and Tfh. These subsets collaborate with other cells to mediate type 1 and type 2 immune responses, characterized by distinct networks of helper T-cell subsets, effector cytokines, and other immune cell types like innate lymphoid cells (ILCs). Additionally, CD4 T cells can become regulatory T cells, which play a crucial role in suppressing autoimmune responses.
Activated T cells also develop into diverse memory cell subsets, which differ in their localization, circulation patterns, and effector functions. These memory cells enable the rapid effector responses observed during secondary immune responses. Despite advancements, significant questions remain regarding the origin, relationships, and molecular mechanisms underlying the development of these memory subsets.
Mature T lymphocytes possess a diverse T-cell receptor (TCR) repertoire that is self-tolerant while being restricted to self-MHC. This delicate balance is achieved through a series of stringent selection processes in the thymus, akin to natural selection in evolution. T cells, or thymocytes, originate from multipotent CD4-CD8- precursors that migrate from the bone marrow to the thymus, where Notch signaling commits them to the T-cell lineage. Immature thymocytes proliferate, upregulate CD4 and CD8, and undergo random TCR gene rearrangements, generating a vast and diverse pool of double-positive (DP) thymocytes, each expressing a unique TCR.
The fate of a DP thymocyte is determined by the affinity of its TCR for self-peptide/MHC complexes encountered while interacting with stromal cells in the thymus's cortex and medulla. DP thymocytes that fail to bind peptide/MHC complexes with sufficient affinity undergo death by neglect, which is the fate of the majority (>90%) of DP thymocytes. Those that bind peptide/MHC complexes with intermediate affinity undergo positive selection, allowing them to travel from the cortex to the medulla and complete maturation into single-positive (SP) CD4 or CD8 T cells. Conversely, DP thymocytes with very high-affinity binding undergo negative selection.
Positive selection occurs exclusively through interactions between thymocytes and cortical thymic epithelial cells (cTECs). In contrast, negative selection is mediated by various cell types in both the cortex and medulla and targets thymocytes during both the DP and SP stages. Notably, medullary thymic epithelial cells (mTECs) uniquely present antigens expressed by other tissues, playing a critical role in eliminating tissue-specific autoreactive T cells from the repertoire. However, the mechanisms that remove autoreactive T cells during development, known as central tolerance, are not entirely foolproof and can leave gaps in immune regulation.
If antigen-presenting cells serve as the bridge between innate and adaptive immunity, then MHC molecules act as the essential tools enabling this connection. These molecules hold antigenic fragments and present them to T-cell receptors, activating the corresponding T cell and initiating the adaptive immune response. As transmembrane proteins, MHC molecules are expressed on the surface of cells and are widely distributed throughout the body. They exhibit significant diversity at both individual and population levels due to evolutionary pressures from pathogens, which have driven gene duplication, polymorphism, and codominant expression patterns. For antigens to associate with MHC molecules, they must first be processed into smaller fragments and transported to cellular locations where they can bind and stabilize the MHC structure before being presented on the cell surface. The shape and chemical properties of the MHC antigen-binding groove, determined by the inherited alleles at this locus, dictate the types of antigenic fragments that can be presented to T cells. This, in turn, determines which portions of infectious agents are recognized and which naïve T cells are activated. Since most B cells, which do not require MHC involvement for antigen recognition, depend on T-cell assistance for full activation, MHC-mediated antigen presentation becomes central to the adaptive immune response. Consequently, diversity in the MHC gene locus benefits individual hosts and enhances species survival by maintaining a diverse MHC gene pool within the population.
Since the early twentieth century, when it was first recognized that antibody molecules could specifically identify and bind to a vast array of antigens, immunologists have sought to understand how a limited amount of genetic information could encode such a broad range of specific receptor molecules in lymphocytes of the adaptive immune response. It is now known that B- and T-cell receptor molecules are encoded by families of short gene segments, which are uniquely recombined in different lymphocytes to create the receptor repertoire of the adaptive immune system.
Receptors in T and B cells consist of two distinct chains that can be recombined in various ways. Additionally, when two receptor gene segments join, further diversity arises through the nontemplated addition of varying numbers of nucleotides at the junctions between segments. These highly variable sequences at the gene segment junctions form the regions on antigen receptors that interact with antigens, known as the complementarity-determining regions. Due to the random addition and deletion of nucleotides at these junctions, many recombined receptor genes fail to encode functional proteins, resulting in the destruction of nascent B and T cells. Thus, the remarkable receptor diversity characteristic of the adaptive immune system demands significant energy expenditure at the cellular level.
The timing of these recombination events is precisely regulated during the development of T and B cells. While the overall process of receptor gene generation is similar in both cell types, subtle variations in the details adapt the receptors to the specific functions of each cell type.
The complement system is a collection of serum proteins, many of which circulate in inactive forms and require cleavage or conformational changes for activation. These proteins include initiator molecules, enzymatic mediators, membrane-binding components (opsonins), inflammatory mediators, membrane attack proteins, complement receptor proteins, and regulatory components. Although complement protein genes predate those encoding adaptive immune system receptors, complement proteins play roles in both innate and adaptive immunity. Key effector functions are performed by proteins such as C1q and C3b, which act as opsonins in phagocytosis by coating microbial surfaces and facilitating recognition by complement-specific receptors on macrophages. Other complement proteins act as anaphylatoxins, promoting increased blood flow and capillary permeability at inflammatory sites. Additionally, the membrane attack complex, formed by certain complement proteins, creates pores in microbial membranes or infected host cells, causing lysis and death. Due to its destructive potential, a robust regulatory system co-evolved with complement proteins to target microbial threats while minimizing host cell damage. The critical role of the complement system in host defense is evident in the variety of microbial strategies developed to evade it, including mimicking or co-opting host regulatory proteins, destroying complement components, or disrupting their interactions with one another or with antibodies. As new pathogens emerge, novel evasion mechanisms continue to develop.