IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 13. Regulation of the Immune Response

GENETIC REGULATION OF THE IMMUNE RESPONSE

It is well established that different individuals respond differently to the same antigen. Family studies on susceptibility to Corynebacterium diphtheriae suggested that resistance or susceptibility to infection can be an inherited trait. This is also supported by data obtained from various strains of guinea pigs showing differential resistance to diphtheria; these differences were shown to be genetically determined. In 1943, Fjord-Scheibel, in selective breeding experiments with guinea pig strains exhibiting high and low immunoreactivity, demonstrated that diphtheria antitoxin production is controlled by a single Gene and is inherited as a dominant Mendelian trait. This study was also the first to establish the dominant inheritance pattern of high immunoreactivity. In the first-generation offspring obtained by crossing animals with high immunoreactivity, 90% produced antitoxin, whereas when low-responding guinea pigs were crossed, it took until the fifth generation to obtain 90% low-responding animals.

The ability to respond to an antigen depends on the MHC haplotype

The Development of inbred, or pure, mouse strains has allowed a more in-depth investigation of genetic factors and definitively proven their role in immunological reactivity. Mice with different MHC haplotypes vary in their capacity for a humoral response to specific Antigens (Fig. 13.16). This function depends on Class II MHC molecules and is antigen-specific: a strain that is a high responder to one antigen may respond poorly to others. MHC genes have been shown to play the most critical role in regulating responses to infectious agents (see Chapters 7 and 9).

Fig. 13.16. Fifteen mouse strains were administered a standard dose of the synthetic antigen (TG)-A-L. Serum antibody levels were determined by antigen-binding activity. Animals with the H-2^b haplotype are high responders, H-2^d show an intermediate response, and H-2^k are low responders. However, response levels are similar in certain strains with different haplotypes, indicating that antibody production is also regulated by genes unlinked to the H-2 complex.

Genes unlinked to the MHC also influence the Immune Response

Significant advances in immunology in recent years—such as elucidating The Structure of class I and II MHC molecules, studying the polymorphism of Amino acid sequences in MHC molecules and its significance for peptide binding, developing molecular Methods to monitor The formation of the T-Cell receptor repertoire, and establishing transgenic mouse technology—have contributed to our understanding of how genetic factors influence the immune response. These factors include not only MHC-linked genes. For example, severe combined immunodeficiency is caused by a deficiency of the recombinase gene, whereas leukocyte adhesion deficiency arises from Mutations in the gene encoding the β₂-integrin subunit and the resulting impaired expression of LFA-1, CR3, and CR4.

MHC-linked immune response genes regulate all immune reactions based on T-cell antigen recognition

As described in previous chapters, the immune response depends on the activation of lymphocyte clones. T Cells recognize an antigen only when it is presented to them as a complex of an antigenic peptide with class I or class II MHC antigens. Therefore, for example, murine CD8⁺ cytotoxic T cells specific for LCMV glycoprotein are capable of lysing only those virus-infected target cells derived from mice compatible with effector cell Donors for class I MHC antigens (Fig. 13.17). The capacity for such recognition develops during ontogeny (Fig. 13.18).

Fig. 13.17. The ability of cytotoxic T (Tc) cells from adult mice (A.TL, CBA, and A/J strains) infected with lymphocytic choriomeningitis virus (LCMV) to lyse virus-infected target cells of H-2^k, H-2^s, and H-2^d haplotypes was investigated. A.TL mice have the H-2K^s, H-2I^k, H-2D^d haplotype, and their Tc cells lyse only those LCMV-infected target cells that share the H-2K^s or H-2D^d haplotype with the effectors. This demonstrates that antiviral Tc cells are restricted by class I MHC antigens, with LCMV cytotoxicity being determined primarily by the H-2D locus. In contrast, in A.TL mice infected with Sendai virus, cytotoxicity is determined mainly by the H-2^k locus. The Importance of genetic restriction in these responses is also supported by experiments using CBA mice infected with LCMV. The finding that the most prominent LCMV-induced cytotoxicity is determined by effector-target cell compatibility at the H-2^d locus is corroborated by studies in A/J mice. Different Viruses can preferentially bind to specific H-2^k or H-2^d molecules on target cells, thereby creating optimal conditions for their presentation to cytotoxic cells.

Fig. 13.18. Irradiated recipient mice of two types (A and B) were injected with donor A × B lymphocytes (Bone Marrow or Spleen cells) to restore hematopoiesis. In this manner, chimeric mice were generated in which lymphocytes were of the donor type (A × B), while all other Tissues were of the recipient type. The animals were then immunized with vaccinia virus, their spleen T cells were isolated, and their cytotoxic activity against type A or type B virus-infected B cells was measured. Cells from mice that received bone marrow cells following irradiation could lyse only target Cells of the same type as the recipient (1 and 2). In contrast, mature lymphocytes from animals that received spleen cells (A × B) were able to lyse target cells of both types, A and B, regardless of the recipient type (3 and 4). These findings can be explained as follows: immature bone marrow stem cells, upon injection into irradiated mice, underwent "education" in the recipient Thymus and subsequently could recognize antigen only in association with MHC molecules of the recipient haplotype. However, mature donor spleen cells were already "educated." In most cases, successful education of donor cells in the recipient thymus requires the donor and recipient to share at least one MHC haplotype with identical class II genes.

The shaping of the peripheral T-lymphocyte repertoire depends both on various autoantigens and on the ability of T cells to bind self-MHC antigens. The capacity of a peptide to form a complex with an MHC molecule is determined by the Amino Acid Sequence of its peptide-binding cleft. We now know that most of the polymorphic amino acid residues of an MHC molecule are located within its peptide-binding groove. Therefore, the high amino acid sequence polymorphism of MHC antigens is crucial for peptide binding and, consequently, for T-cell activation. It has been established that T cells undergo Two Types of Selection during thymic development.

✵ Positive selection is based on the interaction of TCRs with MHC molecules On the surface of cortical thymic epithelial cells.

✵ Negative selection results from high-affinity interactions between TCRs and the MHC–peptide complex presented on bone marrow-derived cells in the thymic medulla.

Positive selection in the thymus involves the selection of T cells based on their ability to recognize antigens presented in the context of self-MHC molecules

Initial studies in this field utilized a complex experimental design involving thymectomy, irradiation, bone marrow reconstitution, and thymus grafting (see Chapter 12). Their results showed that cytotoxic lymphocytes lyse only target cells bearing the same MHC antigens as the cells of the thymus in which the T cells developed. These and other findings suggest that maturing T cells "learn" to recognize antigens only in the context of MHC molecules they initially encountered in the thymus.

This process was clarified by experiments in Transgenic Mice when it became possible to generate Transgenic Animals in which the majority of T cells bear a single antigen-specific receptor. The corresponding antigen can also be expressed as a transgene product. This greatly simplifies the analysis because the T cells under study constitute the major fraction of the T-cell population and can be identified using clonotypic or Vβ-specific Antibodies (Vβ being the variable domain of the TCR complex). For example, transgenic mice can be generated in which T cells predominantly express the TCR of a CD8⁺ Tc clone that recognizes the LCMV glycoprotein in complex with the class I H-2D^b molecule, and these animals can be used to demonstrate positive selection. This TCR is identified using antibodies specific for Vβ8.

Different MHC molecules exert distinct effects on the generation of mature CD8⁺ T cells expressing the transgenic TCR (Fig. 13.19). Positive selection of CD8⁺ T cells with the Vβ8-containing transgenic TCR was observed only in mice expressing the H-2D^b molecule. Thus, positive selection of this receptor occurs only in the presence of the appropriate MHC haplotype. Such selection takes place on The surface of cortical thymic epithelial cells. It is hypothesized that the Peptides mediating positive selection are self-peptides normally present in the thymus.

Fig. 13.19. Thymocytes were obtained from transgenic mice whose CD8⁺ T cells bore a TCR recognizing LCMV in association with the H-2^b molecule. CD4 and CD8 expression on thymocytes was analyzed using a fluorescence-activated cell sorter. During normal development, CD4^-CD8^- cells become CD4⁺CD8⁺ and then differentiate into mature CD4⁺CD8^- or CD4^-CD8⁺ cells, or undergo apoptosis. In the control (non-transgenic mice), the major thymocyte population consisted of CD4⁺CD8⁺ cells, with smaller populations of CD4⁺CD8^- and CD4^-CD8⁺ cells. In transgenic mice expressing the H-2^b allele, positive selection of T cells occurred in the thymus, resulting in a significantly expanded CD4^-CD8⁺ population. Such selection failed to occur in the absence of the H-2^b allele. (The terms "high", "low", ^hi, and ^lo refer to the expression levels of CD markers.)

T cells recognizing autoantigens undergo negative selection

Negative selection via clonal deletion has been demonstrated using Monoclonal Antibodies specific for murine TCR Vβ chains. This approach allowed the identification and quantification of T cells expressing TCRs with a given Vβ chain, and this analysis revealed that in mice expressing I-E, Vβ17a⁺ T cells are deleted in the thymus. The presence of Vβ17a⁺CD4⁺CD8⁺ T cells, but not mature Vβ17a⁺CD4⁺ or Vβ17a⁺CD8.1⁺ T cells, suggested that deletion occurs at the double-positive (CD4⁺CD8⁺) stage of T cell maturation. Furthermore, it was established that deletion requires the expression of an endogenous Ligand In addition to I-E, rather than I-E alone.

Superantigens can induce the complete deletion of entire families of T CELL RECEPTORS

In several mouse strains, the thymus undergoes deletion of entire populations of T cells bearing specific TCRs. For instance, in mice expressing the minor lymphocyte-stimulating antigen Mls-1^a and certain class II MHC molecules, Vβ6⁺ and Vβ8.1⁺ T cells are deleted (Fig. 13.20). The capacity of entire T lymphocyte families to recognize Mls antigens explains the intense proliferative response observed during the co-culture of Mls-incompatible cells. The response to certain antigens involves all T cells expressing specific Vβ chains (Fig. 13.21).

Fig. 13.20. Superantigens can cause clonal deletion of T cells expressing specific Vβ chains. The absolute number of T cells whose TCRs contain a given Vβ chain varies among different mouse strains, yet The phenomenon of superantigen-mediated T cell deletion is manifested in all cases. The table provides quantitative data on clonal deletion in several mouse strains. (SEB, staphylococcal enterotoxin B.)

Fig. 13.21. A significant proportion of T cells expressing the Vβ8.1 chain recognize the Mls-1^a antigen. T cell hybridomas were generated by fusing T lymphoblasts (expressing Vβ8.1 or Vβ8.2) isolated from the Lymph Nodes of B10.BR (Mls-1^b) mice with the BW5147 T-cell thymoma variant (expressing neither Vα nor Vβ). Hybrid cells were isolated by screening with antibodies recognizing Vβ8.1 and (for comparison) Vβ8.2, after which the hybridomas were tested for reactivity against Mls-1^a antigens on the surface of H-2^k stimulator cells. The vast majority of Mls-1^a-reactive hybridomas expressed Vβ8.1, and only a minor fraction expressed Vβ8.2. These results demonstrate that the Vβ8.1 chain plays a primary role in recognizing the Mls-1^a antigen.

Antigens that elicit such a strong response, whether exogenous or endogenous, are termed superantigens. They bind not within the peptide-binding groove of MHC molecules, but directly (without Processing) to class I and class II MHC molecules and TCR β chains (see Chapter II). An example of an exogenous superantigen is staphylococcal enterotoxin B. Mouse T cells responding to this antigen possess a TCR containing either Vβ3 or Vβ8 chains. Mls antigens belong to the class of endogenous superantigens (see Chapter II). However, it has now been established that the presence of Mls antigens is actually determined by endogenous murine mammary tumor viruses (MMTV) encoded by the 3' Long Terminal Repeat in The Genome of these mouse strains. There are many different MMTVs, and mice of each strain carry only some of them in their genome. These endogenous superantigens, expressed in the thymus, induce the deletion (negative selection) of T cells bearing TCRs with Vβ3, Vβ6, or Vβ8.1 chains. To investigate how early thymic selection influences the immune capacity of adult animals, transgenic mice described in the previous section were also utilized (bearing transgenes encoding α and β chains of a TCR specific for MuLV glycoprotein in the context of H-2D^b). Neonatal infection with MuLV induced tolerance in mice, rendering them virus carriers. Analysis of maturing T cell populations in these neonatally infected mice revealed a marked reduction in CD4⁺CD8⁺ T cells—a probable consequence of early developmental clonal deletion (Fig. 13.22). Thus, the peripheral T-lymphocyte repertoire is shaped by a combination of positive and negative selection (Fig. 13.23), both of which consequently influence immunoreactivity.

Fig. 13.22. INDUCTION OF TOLERANCE in transgenic mice varies depending on the antigen. This experiment examined the capacity of cells from transgenic mice expressing a TCR specific for MuLV in the context of H-2D^b molecules to mount proliferative and cytotoxic responses upon interaction with MuLV-infected cells. This TCR also expresses Vβ8.1, allowing The Effect of Mls-1^a on primary responsiveness to MuLV to be assessed. Infecting mice with MuLV at birth reveals the effect of neonatal contact with the antigen recognized by the transgenic TCR. Animals expressing Mls-1^a exhibited a partial reduction in proliferative and cytotoxic responses, whereas contact with the specific antigen at birth resulted in a complete absence of response. Analysis of T cell populations in these animals showed that MuLV-tolerant mice had decreased numbers of CD4⁺CD8⁺ thymocytes and mature CD8⁺ T cells. However, exposure solely to the endogenous superantigen (Mls-1^a) resulted in the deletion of mature CD8⁺ T cells only. These findings indicate that different antigens can induce T cell tolerance at different stages of their development.

Fig. 13.23. CD4⁺CD8⁺ thymocytes interact with thymic stromal cells expressing class I and class II MHC molecules complexed with self-peptides. Cells exhibiting high affinity for self-class I or class II MHC antigens are deleted, as are thymocytes that fail to recognize these antigens. Cells with low affinity for self-class I MHC antigens undergo selection (positive selection), downregulate the CD4 marker, and differentiate into CD8⁺ T cells. In contrast, thymocytes with low affinity for self-class II MHC antigens give rise to the mature CD4⁺ T-lymphocyte population.

MHC-linked genes regulate responses to infectious agents

MHC-linked genes have been shown to play a defined role in shaping responses to infectious agents as well as autoantigens. In some instances, this function is carried out by genes residing within the MHC itself.

Mouse susceptibility to Trichinella spiralis infection is determined by the I-E locus

The initial observation indicating that MHC-linked genes (Ts-1 and Ts-2) can influence immune responses against parasitic infection came from a model of trichinosis caused by Trichinella spiralis. (Notably, this Organism has a complex antigenic composition, expressing different antigens at various stages of its lifecycle, the presentation of which requires the participation of distinct APCs.) When mice of certain recombinant strains were infected with Trichinella spiralis, resistance or susceptibility was found to depend on the I-E locus: mice expressing I-E are susceptible to infection (Fig. 13.24). The response is also influenced by an MHC-linked gene that does not reside within the MHC proper, but is in linkage disequilibrium with it. This gene, designated Ts-2, has been mapped near the TNF gene.

Fig. 13.24. Association of H-2 haplotype and cell-surface I-E expression with susceptibility to Trichinella spiralis infection. The resistance index was calculated as The ratio of parasites recovered after infection with a standard dose to the corresponding value in B10.BR mice [susceptible (susc.) = 0% resistance] and B10.S mice [resistant (resist.) = 100% resistance]. B10 mice exhibit intermediate resistance.

The I-E locus also influences susceptibility to Leishmania donovani

The I-E subregion also affects mouse susceptibility to Leishmania donovani. Studies using H-2-congenic mice established that I-E-expressing mice lack resistance to visceral leishmaniasis. The direct involvement of the I-E product in determining susceptibility to this infection was demonstrated by the administration of anti-I-E antibodies (but not anti-I-A), which enhanced the clearance of parasites from the body. Furthermore, transferring the I-E transgene into mice lacking this locus rendered the animals unable to eradicate parasites localized in The Liver and spleen, unlike wild-type mice of the Background strain.

Certain HLA haplotypes confer protection against Plasmodium falciparum

Studies on the association of HLA haplotypes with severe malarial anemia revealed that the DRB1*1302-DQB1*0501 haplotype, which is common in West African populations and rare in other racial groups, protects against fatal malaria caused by Plasmodium falciparum. It has been shown that DRB1*1302 and DRB1*1301 molecules, which differ by a single amino acid residue in their β chains, bind distinct peptides, and this difference evidently influences the immune response against this malaria parasite.

MHC-linked genes substantially influence susceptibility to autoimmune diseases

Associations with MHC genes. Insulin-dependent Diabetes Mellitus (IDDM), an autoimmune disease characterized by the destruction of pancreatic β cells by The Immune System, is associated with the HLA-DR3 and HLA-DR4 antigens. The highest risk of developing the disease occurs in HLA-DR3/DR4 heterozygotes. In fact, IDDM is associated with DQ genes, although linkage disequilibrium led to the initial identification of an association with DR. Molecular genetic techniques have enabled a more detailed analysis of this association, revealing that in Caucasians the disease is primarily associated with the DQB1*0302 gene. Rheumatoid Arthritis across various ethnic groups is associated predominantly with HLA-DR4 or HLA-DR1 and only infrequently with HLA-DQ. The mechanisms underlying increased susceptibility to these conditions remain unclear. One possible reason for their association with a given haplotype is the variation in class II gene repertoires generated As a result of positive and negative selection. It is also plausible that immune-eliciting epitopes on bacterial or viral surfaces preferentially bind to certain MHC molecules. This hypothesis is supported by amino acid sequence analyses of the peptide-binding grooves of HLA-DR4 and HLA-DR1 molecules: disease-susceptibility and resistance-associated HLA-DR subtypes contain differently charged amino acid residues.

Associations with the MHC region. Another example of linkage disequilibrium is the association of an autoimmune process in (NZB x NZW)F1 mice with the H-2^Z haplotype of the parental NZW strain. It has been clearly established that the disease is associated not with the MHC genes themselves, but rather with the TNFα gene closely linked to the MHC. The TNFα allele in NZW mice determines a low level of TNFα production. When the cytokine concentration increases, the animals acquire resistance to lupus nephritis (Fig. 13.25).

Fig. 13.25.

1. Female (NZW x NZB)F1 mice of the experimental group (n = 20) were treated with recombinant murine TNFα. The control group consisted of F1 mice of the same AGE AND SEX. The survival rates of the experimental and control mice were compared.

2. Cumulative incidence of severe proteinuria (≥300 mg/100 ml) in TNFα-treated (NZW x NZB)F1 mice and control animals.

Associations with genes regulating antigen processing. Other MHC-linked genes capable of influencing the immune response have recently been identified. These genes are involved in the proteolytic Cleavage of antigens into antigenic fragments and in their transport. These genes exhibit functionally significant polymorphism. For instance, in rats, various allelic forms of the cim locus (which encodes the TAP2 protein) determine the efficiency of MHC class I molecule-peptide complex formation, which in turn affects the recognition of these MHC molecules as alloantigens. Thus, it is possible that the established associations of certain diseases with the MHC are driven by such genes, which regulate antigen proteolysis and The transport of antigenic peptides to MHC molecules for presentation to immune system cells.

Many non-MHC genes also modulate immune responses

The immune response is also regulated by several genes located outside the MHC region. However, these genes generally display less polymorphism compared to the MHC; consequently, their contribution to disease susceptibility is not as profound as that of MHC genes. Nevertheless, non-MHC genes can play a significant role in autoimmune diseases, allergies, and infections (Fig. 13.26), as evidenced by the following facts:

✵ Individuals with deficiencies in the C3 Complement component exhibit increased susceptibility to bacterial infections and a predisposition to immune complex disease.

✵ In certain families predisposed to allergies, high levels of IgE production have been found, associated with an "atopy gene" localized on chromosome 11q.

Fig. 13.26. Different mouse strains vary in their resistance to the indicated microorganisms. Strains carrying the same MHC haplotype can be either susceptible or resistant, demonstrating that the MHC haplotype does not play a decisive role in infection resistance.

Non-MHC-linked genes influence susceptibility to infections

Macrophages play a pivotal role in the immune system. Therefore, genes regulating their activity can determine the outcome of many immune reactions. An example of the Genetic regulation of macrophage Functions is the effect of the Lsh/Ity/Bcg gene. This gene regulates the early response to infection with Leishmania donovani, Salmonella typhimurium, Mycobacterium bovis, M. lepraemurium, and M. intracellulare. It affects the early phase of macrophage priming and activation, and is associated with a range of effects, including:

✵ enhanced cellular Respiration,

✵ increased antitumor activity,

✵ enhanced antimicrobial activity, and

✵ elevated expression of MHC class II antigens.

Recent studies have led to the identification of the Nramp gene, which is a potential candidate for the murine Bcg gene. Since Nramp encodes a membrane protein homologous to known transport Proteins, it has been suggested that its expression may affect the transport of NO₂^- into phagolysosomes and thereby influence the destruction of intracellular microorganisms. However, until this gene is experimentally proven (via transfection or transgenesis) to encode the Bcg product, this hypothesis remains purely speculative.

Through selective breeding, two strains of Biozzi mice (named after the researcher who derived them) were obtained, differing in their reactivity levels following immunization with foreign erythrocytes (high- and low-responder animals). One of the Factors Determining the disparate response capacity of these mouse strains to erythrocyte antigens is genetically determined differences in macrophage activity. Immune responses to parasitic infections in high- and low-responder mouse strains also differ significantly, and these differences do not necessarily correlate with The amount of anti-sheep red Blood cell antibodies produced (Fig. 13.27).

Fig. 13.27. The susceptibility of Biozzi mouse strains to parasitic infections varies and does not correlate with their Classification as high- or low-responder lines.

Eosinophils play a crucial role in the body's response to parasitic infections. It has been established that the degree of eosinophilia developing during infection is genetically determined and varies significantly among different mouse strains. A similar phenomenon is observed in guinea pigs and sheep: a pronounced correlation has been found between resistance to nematode infection and the intensity of eosinophilia.

Non-MHC-linked genes influence the development of autoimmune diseases

A major breakthrough in understanding the GENETIC BASIS OF autoimmune pathology was the recent mapping of loci regulating susceptibility to insulin-dependent diabetes mellitus (IDDM). This work was largely performed using NOD mice, which spontaneously develop an autoimmune disease similar to human IDDM. At least 15 genetic loci (Idd1–15) have been mapped in these mice, and only one of them (Idd1) was found to be linked to the MHC on chromosome 17. It is hypothesized that this gene directly encodes MHC class II molecules. Other genes have been mapped to various Chromosomes, but their exact nature and role in Disease resistance or susceptibility remain unknown.

Mice carrying the mutated lpr gene develop a lymphoproliferative disorder with characteristic Clinical Features. These animals produce anti-DNA antibodies and rheumatoid factor, form circulating immune complexes, and develop Glomerulonephritis. They also exhibit lymphadenopathy with a peripheral expansion of CD4^-CD8^- T cells. These T cells are not monoclonal, but possess diverse TCR structures. Initially, a defect in negative selection was proposed to explain this syndrome, though it was difficult to envision how an lpr-like gene could mediate such an effect. It was later discovered that lpr mice harbor a defect in the CD95 (Fas) molecule, the gene for which is located on chromosome 19. Fas is a transmembrane molecule belonging to the TNF receptor superfamily; upon interacting with its ligand, CD95L (FasL), it induces programmed cell death, or apoptosis. CD95L is a member of the tumor necrosis factor and nerve growth factor family. The defect in the Fas antigen caused by the lpr mutation results in a failure of apoptosis. However, this defect apparently does not affect negative selection or the formation of a normal repertoire of mature single-positive T cells in the thymus. Evidently, Fas serves as only one of the ligands mediating apoptosis. It is currently hypothesized that this defect leads to the expansion of double-negative T cells in the periphery and accelerates the autoimmune syndrome. Impaired apoptosis also occurs in B cells, leading to the accumulation of peripheral autoreactive B lymphocytes.

Other studies have established that the gld gene, the presence of which triggers an autoimmune disease similar to that observed in lpr/lpr mice, encodes a defective FasL. Thus, gld/gld mice—which fail to express a functional ligand—similarly exhibit deficient peripheral B- and T-cell apoptosis and the development of autoimmunity. The murine gld gene is localized on chromosome 1, thereby serving as an example of a gene that influences immune function yet is not linked to the MHC. Syndromes similar to those described above also occur in humans and are likewise associated with defects in Fas activity and function.

Questions for Thought

■ Endogenous retroviral sequences modify the expressed T-cell repertoire in the mouse. What is the Biological Significance of this modification?

■ Why does the immune system retain such A large number of diverse mechanisms for regulating the immune response?

■ The Examples of regulation described in this chapter were obtained from studies on artificially engineered model systems. Is it possible to determine the likelihood that they operate in healthy humans?

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